The selection and function of cell type-specific enhancers (original) (raw)
Banerji, J., Rusconi, S. & Schaffner, W. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell27, 299–308 (1981). ArticleCASPubMed Google Scholar
Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet.12, 1725–1735 (2003). CASPubMed Google Scholar
Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet.39, 311–318 (2007). CASPubMed Google Scholar
Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nature Genet.38, 1289–1297 (2006). CASPubMed Google Scholar
Barish, G. D. et al. Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response. Genes Dev.24, 2760–2765 (2010). CASPubMedPubMed Central Google Scholar
John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nature Genet.43, 264–268 (2011). CASPubMed Google Scholar
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime _cis_-regulatory elements required for macrophage and B cell identities. Mol. Cell38, 576–589 (2010). This paper shows that the LDTF PU.1 binds to different loci in different cell types. The loci are marked by H3K4me1, act as beacons for SDTFs binding and drive cell type-specific cellular responses. CASPubMedPubMed Central Google Scholar
Lefterova, M. I. et al. Cell-specific determinants of peroxisome proliferator-activated receptor γ function in adipocytes and macrophages. Mol. Cell. Biol.30, 2078–2089 (2010). CASPubMedPubMed Central Google Scholar
Nielsen, R. et al. Genome-wide profiling of PPARγ:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev.22, 2953–2967 (2008). CASPubMedPubMed Central Google Scholar
Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity32, 317–328 (2010). This paper shows that PU.1 is an LDTF necessary for priming signal-dependent enhancers in macrophages, which defines their transcriptional response to inflammatory stimuli. CASPubMed Google Scholar
Pennacchio, L. A. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature444, 499–502 (2006). CASPubMed Google Scholar
Woolfe, A. et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol.3, e7 (2005). PubMed Google Scholar
Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature459, 108–112 (2009). CASPubMedPubMed Central Google Scholar
Bernstein, B. E. et al. An integrated encyclopedia of DNA elements in the human genome. Nature489, 57–74 (2012). This paper summarizes the work of the ENCODE consortium to annotate functional DNA elements in the human genome. Google Scholar
West, J. A. et al. Nucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming. Nature Commun.5, 4719 (2014). CAS Google Scholar
Chan, H. M. & La Thangue, N. B. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J. Cell Sci.114, 2363–2373 (2001). CASPubMed Google Scholar
De Santa, F. et al. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLoS Biol.8, e1000384 (2010). PubMedPubMed Central Google Scholar
Kim, T.-K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature465, 182–187 (2010). References 19 and 20 report the existence of widespread transcription at enhancers, which correlates with the transcription of neighbouring genes. CASPubMedPubMed Central Google Scholar
Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature480, 490–495 (2011). CASPubMed Google Scholar
Ernst, J. & Kellis, M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nature Biotech.28, 817–825 (2010). CAS Google Scholar
He, H. H. et al. Nucleosome dynamics define transcriptional enhancers. Nature Genet.42, 343–347 (2010). CASPubMed Google Scholar
Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature470, 279–283 (2011). CASPubMed Google Scholar
Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA107, 21931–21936 (2010). CASPubMedPubMed Central Google Scholar
Zentner, G. E., Tesar, P. J. & Scacheri, P. C. Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions. Genome Res.21, 1273–1283 (2011). CASPubMedPubMed Central Google Scholar
Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell49, 825–837 (2013). CASPubMed Google Scholar
Gottgens, B. et al. The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5′ bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol. Cell. Biol.24, 1870–1883 (2004). PubMedPubMed Central Google Scholar
Sanchez, M. et al. An SCL 3′ enhancer targets developing endothelium together with embryonic and adult haematopoietic progenitors. Development126, 3891–3904 (1999). CASPubMed Google Scholar
Delabesse, E. et al. Transcriptional regulation of the SCL locus: identification of an enhancer that targets the primitive erythroid lineage in vivo. Mol. Cell. Biol.25, 5215–5225 (2005). CASPubMedPubMed Central Google Scholar
Zaret, K. S. et al. Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. Cold Spring Harb. Symp. Quant. Biol.73, 119–126 (2008). CASPubMedPubMed Central Google Scholar
Pham, T. H. et al. Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1. Nucleic Acids Res.41, 6391–6402 (2013). CASPubMedPubMed Central Google Scholar
Adams, C. C. & Workman, J. L. Binding of disparate transcriptional activators to nucleosomal DNA is inherently cooperative. Mol. Cell. Biol.15, 1405–1421 (1995). CASPubMedPubMed Central Google Scholar
Boyes, J. & Felsenfeld, G. Tissue-specific factors additively increase the probability of the all-or-none formation of a hypersensitive site. EMBO J.15, 2496–2507 (1996). CASPubMedPubMed Central Google Scholar
Hoffman, B. G. et al. Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver. Genome Res.20, 1037–1051 (2010). CASPubMedPubMed Central Google Scholar
Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell151, 153–166 (2012). CASPubMedPubMed Central Google Scholar
Shlyueva, D. et al. Hormone-responsive enhancer-activity maps reveal predictive motifs, indirect repression, and targeting of closed chromatin. Mol. Cell54, 180–192 (2014). CASPubMed Google Scholar
Xu, J. et al. Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. Dev. Cell.23, 796–811 (2012). CASPubMedPubMed Central Google Scholar
Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell151, 994–1004 (2012). CASPubMedPubMed Central Google Scholar
Scott, E. W., Simon, M. C., Anastasi, J. & Singh, H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science265, 1573–1577 (1994). CASPubMed Google Scholar
Kazemian, M., Pham, H., Wolfe, S. A., Brodsky, M. H. & Sinha, S. Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development. Nucleic Acids Res.41, 8237–8252 (2013). CASPubMedPubMed Central Google Scholar
Heinz, S. et al. Effect of natural genetic variation on enhancer selection and function. Nature503, 487–492 (2013). CASPubMedPubMed Central Google Scholar
Stefflova, K. et al. Cooperativity and rapid evolution of cobound transcription factors in closely related mammals. Cell154, 530–540 (2013). CASPubMedPubMed Central Google Scholar
Trompouki, E. et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell147, 577–589 (2011). CASPubMedPubMed Central Google Scholar
Yanez-Cuna, J. O., Dinh, H. Q., Kvon, E. Z., Shlyueva, D. & Stark, A. Uncovering _cis_-regulatory sequence requirements for context-specific transcription factor binding. Genome Res.22, 2018–2030 (2012). CASPubMedPubMed Central Google Scholar
Mercer, E. M. et al. Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. Immunity35, 413–425 (2011). CASPubMedPubMed Central Google Scholar
Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell147, 565–576 (2011). References 36 and 48 show that SDTFs bind to open chromatin regions that are defined by combinations of LDTFs. CASPubMedPubMed Central Google Scholar
Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell122, 33–43 (2005). CASPubMed Google Scholar
Kaikkonen, M. U. et al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol. Cell51, 310–325 (2013). This paper shows that the SDTF NF-κB contributes to thede novopriming (and activation) of enhancers in conjunction with LDTFs, and that transcription elongation is required for the methylation of the flanking H3K4 by MLL3 and MLL4. CASPubMedPubMed Central Google Scholar
Sullivan, A. L. et al. Serum response factor utilizes distinct promoter- and enhancer-based mechanisms to regulate cytoskeletal gene expression in macrophages. Mol. Cell. Biol.31, 861–875 (2011). CASPubMed Google Scholar
Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell152, 157–171 (2013). This paper describes signal-dependent selection of latent enhancers in macrophages and their persistence after signal termination as a molecular memory of prior activation. CASPubMed Google Scholar
Voss, T. C. et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell146, 544–554 (2011). CASPubMedPubMed Central Google Scholar
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell159, 1327–1340 (2014). CASPubMedPubMed Central Google Scholar
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell159, 1312–1326 (2014). References 54 and 55 demonstrate how specific tissue environments differentially influence the selection and function of enhancers in macrophage populations. CASPubMedPubMed Central Google Scholar
Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell138, 1019–1031 (2009). CASPubMedPubMed Central Google Scholar
Euskirchen, G. M. et al. Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches. PLoS Genet.7, e1002008 (2011). CASPubMedPubMed Central Google Scholar
Morris, S. A. et al. Overlapping chromatin-remodeling systems collaborate genome wide at dynamic chromatin transitions. Nature Struct. Mol. Biol.21, 73–81 (2014). CAS Google Scholar
Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature467, 430–435 (2010). CASPubMedPubMed Central Google Scholar
Siersbaek, R. et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep.7, 1443–1455 (2014). CASPubMed Google Scholar
Rosenfeld, M. G., Lunyak, V. V. & Glass, C. K. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev.20, 1405–1428 (2006). CASPubMed Google Scholar
Blazek, E., Mittler, G. & Meisterernst, M. The mediator of RNA polymerase II. Chromosoma113, 399–408 (2005). CASPubMed Google Scholar
Malik, S. & Roeder, R. G. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nature Rev. Genet.11, 761–772 (2010). CASPubMed Google Scholar
Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell131, 58–69 (2007). CASPubMed Google Scholar
Dey, A., Chitsaz, F., Abbasi, A., Misteli, T. & Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl Acad. Sci. USA100, 8758–8763 (2003). CASPubMedPubMed Central Google Scholar
Koch, F. et al. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nature Struct. Mol. Biol.18, 956–963 (2011). CAS Google Scholar
Zhang, W. et al. Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J. Biol. Chem.287, 43137–43155 (2012). CASPubMedPubMed Central Google Scholar
Collis, P., Antoniou, M. & Grosveld, F. Definition of the minimal requirements within the human β-globin gene and the dominant control region for high level expression. EMBO J.9, 233–240 (1990). CASPubMedPubMed Central Google Scholar
Lam, M. T. et al. Rev–Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature498, 511–515 (2013). CASPubMedPubMed Central Google Scholar
Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature507, 455–461 (2014). CASPubMedPubMed Central Google Scholar
Core, L. J. et al. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nature Genet.46, 1311–1320 (2014). CASPubMed Google Scholar
Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature474, 390–394 (2011). CASPubMedPubMed Central Google Scholar
Kieffer-Kwon, K. R. et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell155, 1507–1520 (2013). CASPubMed Google Scholar
Bonn, S. et al. Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nature Genet.44, 148–156 (2012). CASPubMed Google Scholar
Almada, A. E., Wu, X., Kriz, A. J., Burge, C. B. & Sharp, P. A. Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature499, 360–363 (2013). CASPubMedPubMed Central Google Scholar
Fong, Y. W. & Zhou, Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature414, 929–933 (2001). CASPubMed Google Scholar
Muller-McNicoll, M. & Neugebauer, K. M. How cells get the message: dynamic assembly and function of mRNA-protein complexes. Nature Rev. Genet.14, 275–287 (2013). PubMed Google Scholar
Bieberstein, N. I., Carrillo Oesterreich, F., Straube, K. & Neugebauer, K. M. First exon length controls active chromatin signatures and transcription. Cell Rep.2, 62–68 (2012). CASPubMed Google Scholar
Kowalczyk, M. S. et al. Intragenic enhancers act as alternative promoters. Mol. Cell45, 447–458 (2012). CASPubMed Google Scholar
Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res.22, 1775–1789 (2012). CASPubMedPubMed Central Google Scholar
Schaukowitch, K. et al. Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell56, 29–42 (2014). CASPubMedPubMed Central Google Scholar
Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science322, 1845–1848 (2008). CASPubMedPubMed Central Google Scholar
Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev.26, 2604–2620 (2012). CASPubMedPubMed Central Google Scholar
Lee, J. E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife2, e01503 (2013). PubMedPubMed Central Google Scholar
Sims, R. J. 3rd & Reinberg, D. Histone H3 Lys 4 methylation: caught in a bind? Genes Dev.20, 2779–2786 (2006). CASPubMed Google Scholar
Plank, J. L. & Dean, A. Enhancer function: mechanistic and genome-wide insights come together. Mol. Cell55, 5–14 (2014). CASPubMedPubMed Central Google Scholar
Schmidt, D. et al. A CTCF-independent role for cohesin in tissue-specific transcription. Genome Res.20, 578–588 (2010). CASPubMedPubMed Central Google Scholar
Liu, W. et al. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell155, 1581–1595 (2013). CASPubMedPubMed Central Google Scholar
Nord, A. S. et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell155, 1521–1531 (2013). CASPubMedPubMed Central Google Scholar
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell155, 934–947 (2013). CASPubMed Google Scholar
Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell153, 307–319 (2013). References 91 and 92 describe genomic regions near genes, which are highly enriched for marks of active enhancers and have essential roles in determining cell identity and function. CASPubMedPubMed Central Google Scholar
Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell159, 374–387 (2014). CASPubMedPubMed Central Google Scholar
Parker, S. C. et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl Acad. Sci. USA110, 17921–17926 (2013). CASPubMedPubMed Central Google Scholar
Cremer, T. et al. Chromosome territories — a functional nuclear landscape. Curr. Opin. Cell Biol.18, 307–316 (2006). CASPubMed Google Scholar
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science326, 289–293 (2009). CASPubMedPubMed Central Google Scholar
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature485, 376–380 (2012). CASPubMedPubMed Central Google Scholar
Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature489, 109–113 (2012). References 97 and 98 use global 3C assays to interrogate the 3D organization of functional elements within the genome. CASPubMedPubMed Central Google Scholar
de Laat, W. & Grosveld, F. Spatial organization of gene expression: the active chromatin hub. Chromosome Res.11, 447–459 (2003). CASPubMed Google Scholar
Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature503, 290–294 (2013). CASPubMedPubMed Central Google Scholar
Ghavi-Helm, Y. et al. Enhancer loops appear stable during development and are associated with paused polymerase. Nature512, 96–100 (2014). CASPubMed Google Scholar
Vassetzky, Y., Hair, A. & Mechali, M. Rearrangement of chromatin domains during development in Xenopus. Genes Dev.14, 1541–1552 (2000). CASPubMedPubMed Central Google Scholar
Yan, J. et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell154, 801–813 (2013). CASPubMed Google Scholar
Nagano, T. et al. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature502, 59–64 (2013). CASPubMed Google Scholar
Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell148, 84–98 (2012). This study shows that promoters can function as enhancers. CASPubMedPubMed Central Google Scholar
Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature498, 516–520 (2013). CASPubMedPubMed Central Google Scholar
Bender, M. A. et al. The hypersensitive sites of the murine β-globin locus control region act independently to affect nuclear localization and transcriptional elongation. Blood119, 3820–3827 (2012). CASPubMedPubMed Central Google Scholar
Sur, I. K. et al. Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science338, 1360–1363 (2012). CASPubMed Google Scholar
Rosenbauer, F. et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature Genet.36, 624–630 (2004). CASPubMed Google Scholar
Hong, J. W., Hendrix, D. A. & Levine, M. S. Shadow enhancers as a source of evolutionary novelty. Science321, 1314 (2008). CASPubMedPubMed Central Google Scholar
Barolo, S. Shadow enhancers: frequently asked questions about distributed _cis_-regulatory information and enhancer redundancy. Bioessays34, 135–141 (2012). CASPubMed Google Scholar
Lin, Y. C. et al. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nature Immunol.13, 1196–1204 (2012). CAS Google Scholar
Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP–trait associations. Nucleic Acids Res.42, D1001–D1006 (2014). CASPubMed Google Scholar
Pasquali, L. et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nature Genet.46, 136–143 (2014). CASPubMed Google Scholar
Schaub, M. A., Boyle, A. P., Kundaje, A., Batzoglou, S. & Snyder, M. Linking disease associations with regulatory information in the human genome. Genome Res.22, 1748–1759 (2012). CASPubMedPubMed Central Google Scholar
Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genet.45, 124–130 (2013). CASPubMed Google Scholar
Raj, T. et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science344, 519–523 (2014). CASPubMedPubMed Central Google Scholar
Kilpinen, H. et al. Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science342, 744–747 (2013). CASPubMedPubMed Central Google Scholar
McVicker, G. et al. Identification of genetic variants that affect histone modifications in human cells. Science342, 747–749 (2013). References 118–120 report on the effects of natural genetic variation in humans on the binding of transcription factors and histone modifications that are associated with enhancers and gene expression. CASPubMedPubMed Central Google Scholar
Degner, J. F. et al. DNase I sensitivity QTLs are a major determinant of human expression variation. Nature482, 390–394 (2012). CASPubMedPubMed Central Google Scholar
Gaulton, K. J. et al. A map of open chromatin in human pancreatic islets. Nature Genet.42, 255–259 (2010). CASPubMed Google Scholar
Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science316, 1491–1493 (2007). CASPubMed Google Scholar
Cowper-Sal lari, R. et al. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nature Genet.44, 1191–1198 (2012). CASPubMed Google Scholar
Bauer, D. E. et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science342, 253–257 (2013). CASPubMedPubMed Central Google Scholar
Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR–Cas9 for genome engineering. Cell157, 1262–1278 (2014). CASPubMedPubMed Central Google Scholar