Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3

Seth Frietze, Rui Wang, Lijing Yao, Yu G. Tak, Zhenqing Ye, Malaina Gaddis, Heather Witt, Peggy J. Farnham, Victor X. Jin

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Background: The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines.Results: We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3.Conclusions: Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.

Original languageEnglish (US)
Article numberR52
JournalGenome Biology
Volume13
Issue number9
DOIs
StatePublished - Sep 5 2012
Externally publishedYes

Fingerprint

MCF-7 Cells
genome
Genome
Hep G2 Cells
Transcription Factor 7-Like 2 Protein
Binding Sites
cells
Cell Line
bioinformatics
diabetes
gene
Nucleic Acid Regulatory Sequences
Computational Biology
binding sites
Type 2 Diabetes Mellitus
transcription factors
RNA
cancer
genomics
Transcription Factors

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3. / Frietze, Seth; Wang, Rui; Yao, Lijing; Tak, Yu G.; Ye, Zhenqing; Gaddis, Malaina; Witt, Heather; Farnham, Peggy J.; Jin, Victor X.

In: Genome Biology, Vol. 13, No. 9, R52, 05.09.2012.

Research output: Contribution to journalArticle

Frietze, S, Wang, R, Yao, L, Tak, YG, Ye, Z, Gaddis, M, Witt, H, Farnham, PJ & Jin, VX 2012, 'Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3', Genome Biology, vol. 13, no. 9, R52. https://doi.org/10.1186/gb-2012-13-9-r52
Frietze, Seth ; Wang, Rui ; Yao, Lijing ; Tak, Yu G. ; Ye, Zhenqing ; Gaddis, Malaina ; Witt, Heather ; Farnham, Peggy J. ; Jin, Victor X. / Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3. In: Genome Biology. 2012 ; Vol. 13, No. 9.
@article{d6ca762ee42a4ca2ba4171745444282a,
title = "Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3",
abstract = "Background: The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines.Results: We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3.Conclusions: Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.",
author = "Seth Frietze and Rui Wang and Lijing Yao and Tak, {Yu G.} and Zhenqing Ye and Malaina Gaddis and Heather Witt and Farnham, {Peggy J.} and Jin, {Victor X.}",
year = "2012",
month = "9",
day = "5",
doi = "10.1186/gb-2012-13-9-r52",
language = "English (US)",
volume = "13",
journal = "Genome Biology",
issn = "1465-6914",
publisher = "BioMed Central",
number = "9",

}

TY - JOUR

T1 - Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3

AU - Frietze, Seth

AU - Wang, Rui

AU - Yao, Lijing

AU - Tak, Yu G.

AU - Ye, Zhenqing

AU - Gaddis, Malaina

AU - Witt, Heather

AU - Farnham, Peggy J.

AU - Jin, Victor X.

PY - 2012/9/5

Y1 - 2012/9/5

N2 - Background: The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines.Results: We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3.Conclusions: Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.

AB - Background: The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines.Results: We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3.Conclusions: Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.

UR - http://www.scopus.com/inward/record.url?scp=84865773113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865773113&partnerID=8YFLogxK

U2 - 10.1186/gb-2012-13-9-r52

DO - 10.1186/gb-2012-13-9-r52

M3 - Article

C2 - 22951069

AN - SCOPUS:84865773113

VL - 13

JO - Genome Biology

JF - Genome Biology

SN - 1465-6914

IS - 9

M1 - R52

ER -