Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver (original) (raw)

1. Gordon Robertson4,
2. Bogard Zavaglia1,
3. Mike Beach1,
4. Rebecca Cullum5,
5. Sam Lee5,
6. Galina Soukhatcheva2,
7. Leping Li6,
8. Elizabeth D. Wederell5,
9. Nina Thiessen4,
10. Mikhail Bilenky4,
11. Timothee Cezard4,
12. Angela Tam4,
13. Baljit Kamoh4,
14. Inanc Birol4,
15. Derek Dai2,
16. YongJun Zhao4,
17. Martin Hirst4,
18. C. Bruce Verchere2,
19. Cheryl D. Helgason1,3,
20. Marco A. Marra4,7,
21. Steven J.M. Jones4,7 and
22. Pamela A. Hoodless5,7
23. 1 Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
24. 2 Child and Family Research Institute, British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia V5Z 4H4, Canada;
25. 3 Department of Surgery, University of British Columbia, Vancouver, British Columbia V5Z 4E3, Canada;
26. 4 Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
27. 5 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
28. 6 Biostatistics Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, North Carolina 27709, USA;
29. 7 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Abstract

The liver and pancreas share a common origin and coexpress several transcription factors. To gain insight into the transcriptional networks regulating the function of these tissues, we globally identify binding sites for FOXA2 in adult mouse islets and liver, PDX1 in islets, and HNF4A in liver. Because most eukaryotic transcription factors bind thousands of loci, many of which are thought to be inactive, methods that can discriminate functionally active binding events are essential for the interpretation of genome-wide transcription factor binding data. To develop such a method, we also generated genome-wide H3K4me1 and H3K4me3 localization data in these tissues. By analyzing our binding and histone methylation data in combination with comprehensive gene expression data, we show that H3K4me1 enrichment profiles discriminate transcription factor occupied loci into three classes: those that are functionally active, those that are poised for activation, and those that reflect pioneer-like transcription factor activity. Furthermore, we demonstrate that the regulated presence of H3K4me1-marked nucleosomes at transcription factor occupied promoters and enhancers controls their activity, implicating both tissue-specific transcription factor binding and nucleosome remodeling complex recruitment in determining tissue-specific gene expression. Finally, we apply these approaches to generate novel insights into how FOXA2, PDX1, and HNF4A cooperate to drive islet- and liver-specific gene expression.

Footnotes

• ↵8 Corresponding author.
  E-mail brad.hoffman{at}ubc.ca; fax (604) 875-2373.

• [Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/Traces/sra) under accession no. SRA008281 and are also available for download at http://www.bcgsc.ca/data/histone-modification.]

• Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.104356.109.

• Copyright © 2010 by Cold Spring Harbor Laboratory Press

Freely available online through the Genome Research Open Access option.