Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver.
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.
Hoffman
Brad G
BG
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. brad.hoffman@ubc.ca
Robertson
Gordon
G
Zavaglia
Bogard
B
Beach
Mike
M
Cullum
Rebecca
R
Lee
Sam
S
Soukhatcheva
Galina
G
Li
Leping
L
Wederell
Elizabeth D
ED
Thiessen
Nina
N
Bilenky
Mikhail
M
Cezard
Timothee
T
Tam
Angela
A
Kamoh
Baljit
B
Birol
Inanc
I
Dai
Derek
D
Zhao
Yongjun
Y
Hirst
Martin
M
Verchere
C Bruce
CB
Helgason
Cheryl D
CD
Marra
Marco A
MA
Jones
Steven J M
SJ
Hoodless
Pamela A
PA
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D020869:Gene Expression Profiling; D056426:Genetic Loci; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics* / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
C496503:Foxa2 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; C496593:Hnf4a protein, mouse; D018398:Homeodomain Proteins; D009707:Nucleosomes; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051542:Hepatocyte Nuclear Factor 3-beta