Epigenetic modulators, modifiers and mediators in cancer aetiology and progression (original) (raw)

• Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 7, 21–33 (2006). This is the model suggesting that some genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, causing altered differentiation throughout tumour evolution; the current Review revisits this model.
  Article CAS PubMed Google Scholar
• Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
  Article CAS PubMed Google Scholar
• Lee, R. S. et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983–2988 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mack, S. C. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014). This paper reported an absence of recurrent mutations in a subtype of paediatric posterior fossa ependymoma, suggesting the existence of alternative, non-mutational mechanisms for cancer initiation.
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329–334 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Pugh, T. J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).
  Article CAS PubMed Google Scholar
• Shen, H. & Laird, P. W. Interplay between the cancer genome and epigenome. Cell 153, 38–55 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Plass, C. et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet. 14, 765–780 (2013).
  Article CAS PubMed Google Scholar
• Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).
  Article CAS PubMed Google Scholar
• Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43, 309–315 (2011).
  Article CAS PubMed Google Scholar
• Couronne, L., Bastard, C. & Bernard, O. A. TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012).
  Article CAS PubMed Google Scholar
• Grossmann, V. et al. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 52, 410–422 (2013).
  Article CAS PubMed Google Scholar
• Ribeiro, A. F. et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood 119, 5824–5831 (2012).
  Article CAS PubMed Google Scholar
• Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2012).
  Article CAS Google Scholar
• Challen, G. A. et al. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15, 350–364 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Mayle, A. et al. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125, 629–638 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Celik, H. et al. Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. Blood 125, 619–628 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38 (2011).
  Article CAS PubMed Google Scholar
• Abdel-Wahab, O. et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114, 144–147 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Langemeijer, S. M. et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41, 838–842 (2009).
  Article CAS PubMed Google Scholar
• Chou, W. C. et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 118, 3803–3810 (2011).
  Article CAS PubMed Google Scholar
• Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Itzykson, R. et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 121, 2186–2198 (2013).
  Article CAS PubMed Google Scholar
• Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Madzo, J. et al. Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. Cell Rep. 6, 231–244 (2014).
  Article CAS PubMed Google Scholar
• Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).
  CAS PubMed Google Scholar
• Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43, 830–837 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Beguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).
  Article CAS PubMed Google Scholar
• Nikoloski, G. et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42, 665–667 (2010).
  Article CAS PubMed Google Scholar
• Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013).
  Article CAS PubMed Google Scholar
• Simon, C. et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 26, 651–656 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat. Cell Biol. 9, 804–812 (2007).
  Article CAS PubMed Google Scholar
• Martinez-Garcia, E. et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117, 211–220 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Jaffe, J. D. et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45, 1386–1391 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
  CAS PubMed PubMed Central Google Scholar
• Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Mar, B. G. et al. Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat. Commun. 5, 3469 (2014).
  Article PubMed CAS Google Scholar
• Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 (1993). This and the next paper represent the discovery of altered imprinting in cancer.
  Article CAS PubMed Google Scholar
• Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749–751 (1993). This and the previous paper represent the discovery of altered imprinting in cancer.
  Article CAS PubMed Google Scholar
• Zhan, S., Shapiro, D. N. & Helman, L. J. Activation of an imprinted allele of the insulin-like growth factor II gene implicated in rhabdomyosarcoma. J. Clin. Invest. 94, 445–448 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Rainier, S., Dobry, C. J. & Feinberg, A. P. Loss of imprinting in hepatoblastoma. Cancer Res. 55, 1836–1838 (1995).
  CAS PubMed Google Scholar
• Levine, A. J. et al. Genetic variation in insulin pathway genes and distal colorectal adenoma risk. Int. J. Colorectal Dis. 27, 1587–1595 (2012).
  Article PubMed Google Scholar
• Falls, J. G., Pulford, D. J., Wylie, A. A. & Jirtle, R. L. Genomic imprinting: implications for human disease. Am. J. Pathol. 154, 635–647 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Hassan, A. B. & Howell, J. A. Insulin-like growth factor II supply modifies growth of intestinal adenoma in Apc(Min/+) mice. Cancer Res. 60, 1070–1076 (2000).
  CAS PubMed Google Scholar
• Bjornsson, H. T. et al. Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors. J. Natl Cancer Inst. 99, 1270–1273 (2007).
  Article CAS PubMed Google Scholar
• Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005).
  Article CAS PubMed Google Scholar
• Shan, J. et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology 56, 1004–1014 (2012).
  Article CAS PubMed Google Scholar
• DeBaun, M. R. et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am. J. Hum. Genet. 70, 604–611 (2002). This paper showed that epigenetic changes can precede and specifically confer risk of cancer, providing epigenetic epidemiological causal evidence similar to Li-Fraumeni and p53 mutations for genetic epidemiology.
  Article CAS PubMed PubMed Central Google Scholar
• Ferron, S. R. et al. Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis. Nat. Commun. 6, 8265 (2015).
  Article CAS PubMed Google Scholar
• Venkatraman, A. et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345–349 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ziegler, A. N. et al. IGF-II promotes stemness of neural restricted precursors. Stem Cells 30, 1265–1276 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, L. et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood 110, 4111–4119 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Fischedick, G. et al. Nanog induces hyperplasia without initiating tumors. Stem Cell Res. 13, 300–315 (2014).
  Article CAS PubMed Google Scholar
• Lengner, C. J. et al. Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1, 403–415 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Marucci, L. et al. Beta-catenin fluctuates in mouse ESCs and is essential for Nanog-mediated reprogramming of somatic cells to pluripotency. Cell Rep. 8, 1686–1696 (2014).
  Article CAS PubMed Google Scholar
• Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat. Genet. 41, 1350–1353 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, X., Mazur, S. J., Lin, T., Appella, E. & Xu, Y. The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene 33, 2655–2664 (2014).
  Article CAS PubMed Google Scholar
• Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677 (2014). This paper provided a link between reprogramming and oncogenic transformation, showing that transient expression of reprogramming factors in an in vivo mouse model leads to tumour development in various tissues in the absence of irreversible genetic transformation.
  Article CAS PubMed Google Scholar
• Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).
  Article CAS PubMed Google Scholar
• Du, J., Johnson, L. M., Jacobsen, S. E. & Patel, D. J. DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell Biol. 16, 519–532 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Wen, B., Wu, H., Shinkai, Y., Irizarry, R. A. & Feinberg, A. P. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat. Genet. 41, 246–250 (2009). This paper showed that large areas of heterochromatin expand during differentiation and can distinguish cell types.
  Article CAS PubMed PubMed Central Google Scholar
• Tonge, P. D. et al. Divergent reprogramming routes lead to alternative stem-cell states. Nature 516, 192–197 (2014).
  Article CAS PubMed Google Scholar
• Shakya, A. et al. Pluripotency transcription factor Oct4 mediates stepwise nucleosome demethylation and depletion. Mol. Cell. Biol. 35, 1014–1025 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Gidekel, S., Pizov, G., Bergman, Y. & Pikarsky, E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361–370 (2003).
  Article CAS PubMed Google Scholar
• Lee, B. K. et al. Tgif1 counterbalances the activity of core pluripotency factors in mouse embryonic stem cells. Cell Rep. 13, 52–60 (2015).
  Article CAS PubMed Google Scholar
• Rudin, C. M. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 44, 1111–1116 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bass, A. J. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat. Genet. 41, 1238–1242 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Luo, W. et al. Embryonic stem cells markers SOX2, OCT4 and Nanog expression and their correlations with epithelial-mesenchymal transition in nasopharyngeal carcinoma. PLoS ONE 8, e56324 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Chiou, S. H. et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 70, 10433–10444 (2010).
  Article CAS PubMed Google Scholar
• Wang, D. et al. Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients. Oncotarget 5, 10803–10815 (2014).
  PubMed PubMed Central Google Scholar
• Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).
  Article CAS PubMed Google Scholar
• Friedmann-Morvinski, D. & Verma, I. M. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 15, 244–253 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Medema, J. P. Cancer stem cells: the challenges ahead. Nat. Cell Biol. 15, 338–344 (2013).
  Article CAS PubMed Google Scholar
• Kai, K. et al. Maintenance of HCT116 colon cancer cell line conforms to a stochastic model but not a cancer stem cell model. Cancer Sci. 100, 2275–2282 (2009).
  Article CAS PubMed Google Scholar
• Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
  Article CAS PubMed Google Scholar
• Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
  Article CAS PubMed Google Scholar
• Friedmann-Morvinski, D. et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338, 1080–1084 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
  Article CAS PubMed Google Scholar
• Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).
  Article CAS PubMed Google Scholar
• Kikushige, Y. et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20, 246–259 (2011).
  Article CAS PubMed Google Scholar
• Chen, W. J. et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 5, 3472 (2014).
  Article CAS PubMed Google Scholar
• Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
  Article CAS PubMed Google Scholar
• Borovski, T. et al. Tumor microvasculature supports proliferation and expansion of glioma-propagating cells. Int. J. Cancer 125, 1222–1230 (2009).
  Article CAS PubMed Google Scholar
• Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
  Article CAS PubMed Google Scholar
• Badeaux, A. I. & Shi, Y. Emerging roles for chromatin as a signal integration and storage platform. Nat. Rev. Mol. Cell Biol. 14, 211–224 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Kolybaba, A. & Classen, A. K. Sensing cellular states – signaling to chromatin pathways targeting Polycomb and Trithorax group function. Cell Tissue Res. 356, 477–493 (2014).
  Article PubMed Google Scholar
• Wu, B. K. & Brenner, C. Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep. 9, 1827–1840 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Gazin, C., Wajapeyee, N., Gobeil, S., Virbasius, C. M. & Green, M. R. An elaborate pathway required for Ras-mediated epigenetic silencing. Nature 449, 1073–1077 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Wajapeyee, N., Malonia, S. K., Palakurthy, R. K. & Green, M. R. Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors. Genes Dev. 27, 2221–2226 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Serra, R. W., Fang, M., Park, S. M., Hutchinson, L. & Green, M. R. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. eLife 3, e02313 (2014).
  Article PubMed PubMed Central Google Scholar
• Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).
  CAS PubMed PubMed Central Google Scholar
• Nguyen, L. V. et al. Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells. Nature 528, 267–271 (2015). This paper describes the development of phenotypically heterogeneous, serially transplantable tumours from basal cells and luminal progenitors transduced with oncogenic KRAS.
  Article CAS PubMed Google Scholar
• Trosko, J. E. & Tai, M. H. Adult stem cell theory of the multi-stage, multi-mechanism theory of carcinogenesis: role of inflammation on the promotion of initiated stem cells. Contrib. Microbiol. 13, 45–65 (2006).
  Article PubMed Google Scholar
• Suman, S. et al. Current perspectives of molecular pathways involved in chronic Inflammation-mediated breast cancer. Biochem. Biophys. Res. Commun. http://dx.doi.org/10.1016/j.bbrc.2015.10.133 (2015).
• Barham, W. et al. Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ. BMC Cancer 15, 647 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Levy, D. E. & Darnell, J. E. Jr. Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3, 651–662 (2002).
  Article CAS PubMed Google Scholar
• Do, D. V. et al. A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev. 27, 1378–1390 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Tyagi, N. et al. p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer Lett. 370, 260–267 (2016).
  Article CAS PubMed Google Scholar
• Hutchins, A. P., Diez, D. & Miranda-Saavedra, D. Genomic and computational approaches to dissect the mechanisms of STAT3's universal and cell type-specific functions. JAKSTAT 2, e25097 (2013).
  PubMed PubMed Central Google Scholar
• Abu-Remaileh, M. et al. Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. Cancer Res. 75, 2120–2130 (2015).
  Article CAS PubMed Google Scholar
• De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094 (2007).
  Article CAS PubMed Google Scholar
• Lee, J. et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151, 547–558 (2012). The paper showed that the activation of innate immunity enhances the reprogramming efficiency of Yamanaka factors.
  Article CAS PubMed PubMed Central Google Scholar
• Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol. Cell 18, 447–459 (2005).
  Article CAS PubMed Google Scholar
• Bora-Singhal, N. et al. YAP1 regulates OCT4 activity and SOX2 expression to facilitate self-renewal and vascular mimicry of stem-like cells. Stem Cells 33, 1705–1718 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Zhu, J. et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525, 206–211 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Pfister, N. T. et al. Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. Genes Dev. 29, 1298–1315 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Rai, K. et al. DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. Cell 142, 930–942 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). This paper is a good example of metabolic epigenetic modulation by a tumour suppressor gene.
  Article CAS PubMed PubMed Central Google Scholar
• Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Heyn, H. et al. Distinct DNA methylomes of newborns and centenarians. Proc. Natl Acad. Sci. USA 109, 10522–10527 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
  Article PubMed PubMed Central Google Scholar
• Florath, I., Butterbach, K., Muller, H., Bewerunge-Hudler, M. & Brenner, H. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum. Mol. Genet. 23, 1186–1201 (2014).
  Article CAS PubMed Google Scholar
• Yuan, T. et al. An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging. PLoS Genet. 11, e1004996 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Teschendorff, A. E., West, J. & Beck, S. Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Hum. Mol. Genet. 22, R7–R15 (2013). The authors intriguingly argue that epigenetic drift has an evolutionary advantage.
  Article CAS PubMed PubMed Central Google Scholar
• Sun, D. et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673–688 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Benayoun, B. A., Pollina, E. A. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat. Rev. Mol. Cell Biol. 16, 593–610 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Siebold, A. P. et al. Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc. Natl Acad. Sci. USA 107, 169–174 (2010).
  Article CAS PubMed Google Scholar
• Greer, E. L. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, W. et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348, 1160–1163 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res. 23, 260–269 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Riedel, C. G. et al. DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat. Cell Biol. 15, 491–501 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson, M. J., Shivapurkar, N. & Poirier, L. A. Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet. Biochem. J. 218, 987–990 (1984).
  Article CAS PubMed PubMed Central Google Scholar
• Ghoshal, A. K. & Farber, E. The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis 5, 1367–1370 (1984).
  Article CAS PubMed Google Scholar
• Bhave, M. R., Wilson, M. J. & Poirier, L. A. c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 9, 343–348 (1988).
  Article CAS PubMed Google Scholar
• Pogribny, I. P. et al. Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res. 55, 1894–1901 (1995).
  CAS PubMed Google Scholar
• Giovannucci, E. et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J. Natl Cancer Inst. 85, 875–884 (1993).
  Article CAS PubMed Google Scholar
• Ciappio, E. D., Mason, J. B. & Crott, J. W. Maternal one-carbon nutrient intake and cancer risk in offspring. Nutr. Rev. 69, 561–571 (2011).
  Article PubMed Google Scholar
• Choi, S. W. et al. Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. J. Nutr. 129, 1945–1950 (1999).
  Article CAS PubMed Google Scholar
• van Engeland, M. et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res. 63, 3133–3137 (2003).
  CAS PubMed Google Scholar
• Cortessis, V. K. et al. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum. Genet. 131, 1565–1589 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zochbauer-Muller, S. et al. Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. Int. J. Cancer 107, 612–616 (2003).
  Article CAS PubMed Google Scholar
• Russo, A. L. et al. Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer. Clin. Cancer Res. 11, 2466–2470 (2005).
  Article CAS PubMed Google Scholar
• Bollati, V. et al. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 67, 876–880 (2007).
  Article CAS PubMed Google Scholar
• Maekita, T. et al. High levels of aberrant DNA methylation in _Helicobacter pylori_-infected gastric mucosae and its possible association with gastric cancer risk. Clin. Cancer Res. 12, 989–995 (2006).
  Article CAS PubMed Google Scholar
• Chan, A. O. et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut 55, 463–468 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Christensen, B. C. et al. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer Res. 69, 227–234 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Pujadas, E. & Feinberg, A. P. Regulated noise in the epigenetic landscape of development and disease. Cell 148, 1123–1131 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hansen, K. D. et al. Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. Genome Res. 24, 177–184 (2014). This paper showed the link between hypomethylated blocks, variable gene expression, and heterochromatin LOCKs/LADs in cancer.
  Article CAS PubMed PubMed Central Google Scholar
• Meuleman, W. et al. Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res. 23, 270–280 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Banerji, C. R. et al. Cellular network entropy as the energy potential in Waddington's differentiation landscape. Sci. Rep. 3, 3039 (2013).
  Article PubMed PubMed Central Google Scholar
• Chen, X. et al. G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 26, 2499–2511 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, N. et al. Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability. Genes Dev. 29, 379–393 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Ahmed, K. et al. Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo. PLoS One 5, e10531 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Therizols, P. et al. Chromatin decondensation is sufficient to alter nuclear organization in embryonic stem cells. Science 346, 1238–1242 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Eskeland, R. et al. Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol. Cell 38, 452–464 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Vallot, C., Herault, A., Boyle, S., Bickmore, W. A. & Radvanyi, F. PRC2-independent chromatin compaction and transcriptional repression in cancer. Oncogene 34, 741–751 (2015).
  Article CAS PubMed Google Scholar
• Lemaitre, C. & Bickmore, W. A. Chromatin at the nuclear periphery and the regulation of genome functions. Histochem. Cell Biol. 144, 111–122 (2015).
  Article CAS PubMed Google Scholar
• Burke, B. & Stewart, C. L. The nuclear lamins: flexibility in function. Nat. Rev. Mol. Cell Biol. 14, 13–24 (2013).
  Article CAS PubMed Google Scholar
• Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Harr, J. C. et al. Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. J. Cell Biol. 208, 33–52 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Towbin, B. D. et al. Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150, 934–947 (2012).
  Article CAS PubMed Google Scholar
• Guarda, A., Bolognese, F., Bonapace, I. M. & Badaracco, G. Interaction between the inner nuclear membrane lamin B receptor and the heterochromatic methyl binding protein, MeCP2. Exp. Cell Res. 315, 1895–1903 (2009).
  Article CAS PubMed Google Scholar
• Schooley, A., Moreno-Andres, D., De Magistris, P., Vollmer, B. & Antonin, W. The lysine demethylase LSD1 is required for nuclear envelope formation at the end of mitosis. J. Cell Sci. 128, 3466–3477 (2015).
  Article CAS PubMed Google Scholar
• Montes de Oca, R., Shoemaker, C. J., Gucek, M., Cole, R. N. & Wilson, K. L. Barrier-to-autointegration factor proteome reveals chromatin-regulatory partners. PLoS One 4, e7050 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Demmerle, J., Koch, A. J. & Holaska, J. M. The nuclear envelope protein emerin binds directly to histone deacetylase 3 (HDAC3) and activates HDAC3 activity. J. Biol. Chem. 287, 22080–22088 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Somech, R. et al. The nuclear-envelope protein and transcriptional repressor LAP2β interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J. Cell Sci. 118, 4017–4025 (2005).
  Article CAS PubMed Google Scholar
• Holaska, J. M. & Wilson, K. L. An emerin “proteome”: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechanosensing, and nuclear architecture. Biochemistry 46, 8897–8908 (2007).
  Article CAS PubMed Google Scholar
• Finlan, L. E. et al. Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet. 4, e1000039 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Melcer, S. et al. Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Nat. Commun. 3, 910 (2012).
  Article PubMed CAS Google Scholar
• Adamo, A. et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat. Cell Biol. 13, 652–659 (2011).
  Article CAS PubMed Google Scholar
• Ma, D. K., Chiang, C. H., Ponnusamy, K., Ming, G. L. & Song, H. G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells. Stem Cells 26, 2131–2141 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sadaie, M. et al. Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev. 27, 1800–1808 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Zane, L., Sharma, V. & Misteli, T. Common features of chromatin in aging and cancer: cause or coincidence? Trends Cell Biol. 24, 686–694 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Shankar, S. R. et al. G9a, a multipotent regulator of gene expression. Epigenetics 8, 16–22 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• McDonald, O. G., Wu, H., Timp, W., Doi, A. & Feinberg, A. P. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat. Struct. Mol. Biol. 18, 867–874 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Feinberg, A. P. & Irizarry, R. A. Evolution in health and medicine Sackler colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc. Natl Acad. Sci. USA 107 (Suppl. 1), 1757–1764 (2010).
  Article CAS PubMed Google Scholar
• Timp, W. & Feinberg, A. P. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13, 497–510 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ohlsson, R. et al. Epigenetic variability and the evolution of human cancer. Adv. Cancer Res. 88, 145–168 (2003).
  Article CAS PubMed Google Scholar
• Hansen, K. D. et al. Increased methylation variation in epigenetic domains across cancer types. Nat. Genet. 43, 768–775 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Timp, W. et al. Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors. Genome Med. 6, 61 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2012).
  Article CAS Google Scholar
• Teschendorff, A. E. et al. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 4, 24 (2012). This paper showed that epigenetic variability in normal tissue predicts the development of later cancers.
  Article CAS PubMed PubMed Central Google Scholar
• Teschendorff, A. E. & Widschwendter, M. Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions. Bioinformatics 28, 1487–1494 (2012).
  Article CAS PubMed Google Scholar
• Dinalankara, W. & Bravo, H. C. Gene expression signatures based on variability can robustly predict tumor progression and prognosis. Cancer Inform. 14, 71–81 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Vandiver, A. R. et al. Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol. 16, 80 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Teschendorff, A. E., Banerji, C. R., Severini, S., Kuehn, R. & Sollich, P. Increased signaling entropy in cancer requires the scale-free property of protein interaction networks. Sci. Rep. 5, 9646 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Kumar, R. M. et al. Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature 516, 56–61 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Singer, Z. S. et al. Dynamic heterogeneity and DNA methylation in embryonic stem cells. Mol. Cell 55, 319–331 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Landan, G. et al. Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues. Nat. Genet. 44, 1207–1214 (2012). This paper demonstrated stochastic epipolymorphisms in cancer.
  Article CAS PubMed Google Scholar
• Reddy, K. L. & Feinberg, A. P. Higher order chromatin organization in cancer. Semin. Cancer Biol. 23, 109–115 (2013).
  Article CAS PubMed Google Scholar
• Carone, D. M. & Lawrence, J. B. Heterochromatin instability in cancer: from the Barr body to satellites and the nuclear periphery. Semin. Cancer Biol. 23, 99–108 (2013).
  Article CAS PubMed Google Scholar
• Kind, J. et al. Single-cell dynamics of genome-nuclear lamina interactions. Cell 153, 178–192 (2013).
  Article CAS PubMed Google Scholar
• Schlimgen, R. J., Reddy, K. L., Singh, H. & Krangel, M. S. Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments. Nat. Immunol. 9, 802–809 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, H. et al. PARP1- and CTCF-mediated interactions between active and repressed chromatin at the lamina promote oscillating transcription. Mol. Cell 59, 984–997 (2015).
  Article CAS PubMed Google Scholar
• Wassef, M. et al. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. Genes Dev. 29, 2547–2562 (2015).
  PubMed PubMed Central Google Scholar
• Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).
  Article CAS PubMed Google Scholar
• Boros, J., Arnoult, N., Stroobant, V., Collet, J. F. & Decottignies, A. Polycomb repressive complex 2 and H3K27me3 cooperate with H3K9 methylation to maintain heterochromatin protein 1alpha at chromatin. Mol. Cell. Biol. 34, 3662–3674 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Hnisz, D. et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol. Cell 58, 362–370 (2015). The paper showed that super-enhancers integrate developmental cues and oncogenic signalling pathways to regulate genes that control cell identity or tumour development.
  Article CAS PubMed PubMed Central Google Scholar
• Bahar Halpern, K. et al. Bursty gene expression in the intact mammalian liver. Mol. Cell 58, 147–156 (2015).
  Article CAS PubMed Google Scholar
• Lam, A. & Deans, T. L. A noisy tug of war: the battle between transcript production and degradation in the liver. Dev. Cell 33, 3–4 (2015).
  Article CAS PubMed Google Scholar
• Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Noordermeer, D. et al. Variegated gene expression caused by cell-specific long-range DNA interactions. Nat. Cell Biol. 13, 944–951 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Whyte, W. A. et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Dey, A., Nishiyama, A., Karpova, T., McNally, J. & Ozato, K. Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol. Biol. Cell 20, 4899–4909 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Adam, R. C. et al. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521, 366–370 (2015). This paper showed that the microenvironment dynamically reprogrammes the location of super-enhancers in follicular stem cells.
  Article CAS PubMed PubMed Central Google Scholar
• Gomez-Diaz, E. & Corces, V. G. Architectural proteins: regulators of 3D genome organization in cell fate. Trends Cell Biol. 24, 703–711 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015). This paper showed that disruption of TAD structure can result in pathological long-range enhancer–promoter interactions and disease.
  Article CAS PubMed PubMed Central Google Scholar
• Kanduri, C. et al. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr. Biol. 10, 853–856 (2000).
  Article CAS PubMed Google Scholar
• Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014). This paper used multi-region sequencing to analyse tumour evolution in renal cell carcinoma and reported distinct, spatially separated mutations converging on modifiers of specific histone marks.
  Article CAS PubMed PubMed Central Google Scholar
• Yildirim, E., Sadreyev, R. I., Pinter, S. F. & Lee, J. T. X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription. Nat. Struct. Mol. Biol. 19, 56–61 (2012).
  Article CAS Google Scholar
• Stephens, A. D. et al. Pericentric chromatin loops function as a nonlinear spring in mitotic force balance. J. Cell Biol. 200, 757–772 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Pang, B., de Jong, J., Qiao, X., Wessels, L. F. & Neefjes, J. Chemical profiling of the genome with anti-cancer drugs defines target specificities. Nat. Chem. Biol. 11, 472–480 (2015).
  Article CAS PubMed Google Scholar
• Cheng, J. et al. Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells. Nat. Commun. 6, 7209 (2015).
  Article PubMed Google Scholar
• Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nat. Genet. 44, 1321–1325 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Fujimoto, A. et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet. 44, 760–764 (2012).
  Article CAS PubMed Google Scholar
• Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
• Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Smith, M. J. et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat. Genet. 45, 295–298 (2013).
  Article CAS PubMed Google Scholar
• Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
  Article CAS PubMed Google Scholar
• Kolla, V., Zhuang, T., Higashi, M., Naraparaju, K. & Brodeur, G. M. Role of CHD5 in human cancers: 10 years later. Cancer Res. 74, 652–658 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
  Article CAS PubMed Google Scholar
• Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Tahara, T. et al. Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators. Gastroenterology 146, 530–538 e5 (2014).
  Article CAS PubMed Google Scholar
• Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Le Gallo, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat. Genet. 44, 1310–1315 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Neumann, M. et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 121, 4749–4752 (2013).
  Article CAS PubMed Google Scholar
• Kanai, Y., Ushijima, S., Nakanishi, Y., Sakamoto, M. & Hirohashi, S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett. 192, 75–82 (2003).
  Article CAS PubMed Google Scholar
• Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).
  Article PubMed Google Scholar
• Scourzic, L., Mouly, E. & Bernard, O. A. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 7, 9 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Krauthammer, M. et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat. Genet. 44, 1006–1014 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ward, R., Johnson, M., Shridhar, V., van Deursen, J. & Couch, F. J. CBP truncating mutations in ovarian cancer. J. Med. Genet. 42, 514–518 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ropero, S. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat. Genet. 38, 566–569 (2006).
  Article CAS PubMed Google Scholar
• Hanigan, C. L. et al. An inactivating mutation in HDAC2 leads to dysregulation of apoptosis mediated by APAF1. Gastroenterology 135, 1654–1664 (2008).
  Article CAS PubMed Google Scholar
• Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).
  Article CAS PubMed Google Scholar
• Thirman, M. J. et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N. Engl. J. Med. 329, 909–914 (1993).
  Article CAS PubMed Google Scholar
• Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7, 823–833 (2007).
  Article CAS PubMed Google Scholar
• Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Zang, Z. J. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 44, 570–574 (2012).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Vougiouklakis, T., Hamamoto, R., Nakamura, Y. & Saloura, V. The NSD family of protein methyltransferases in human cancer. Epigenomics 7, 863–874 (2015).
  Article CAS PubMed Google Scholar
• Fontebasso, A. M. et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125, 659–669 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Van Vlierberghe, P. et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia 25, 130–134 (2011).
  Article CAS PubMed Google Scholar
• Van Vlierberghe, P. et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat. Genet. 42, 338–342 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).
  Article PubMed CAS Google Scholar
• Wang, G. G. et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847–851 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• French, C. A. et al. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am. J. Pathol. 159, 1987–1992 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Pena, P. V. et al. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).
  Article CAS PubMed Google Scholar
• Li, H. et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood 123, 1487–1498 (2014).
  Article CAS PubMed PubMed Central Google Scholar