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

Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsOur studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

“…Transcription of some genes may be directly regulated by TCF7L2 binding to their promoter and/or enhancer sequences, as has been reported for PCK1 and GYS2, while others (G6PC) have not been reported to have TCF7L2 recognition sites [21,[31][32][33]. Therefore, we analysed the role of TCF7L2 in the HNF4α-FOXO1-mediated transcriptional regulation of G6PC.…”

“…Two specific TCF7L2 isoforms interact with HNF4α protein No direct TCF7L2 binding on the G6PC promoter region was reported in ChIP binding studies [21,[31][32][33]. Therefore, we hypothesised that TCF7L2 could regulate G6PC transcription by interacting with HNF4α protein.…”

Specification of osteoblast cell fate by canonical Wnt signaling requires Bmp2

“…The USCS Genome Browser (Kent et al, 2002) was used to examine the genetic locus of murine Grhl3 (Fig. S3A) and revealed two consensus Tcf/Lefbinding sites (Cadigan and Waterman, 2012;Frietze et al, 2012;Guenther et al, 2014) in regions of high to medium genomic conservation in vertebrates (Fig. S3B,C).…”

GC skew defines distinct RNA polymerase pause sites in CpG island promoters

“…The following data sets were used in this study: for MCF7 cells, ChIP-seq of Pol II (GSM365929) (Welboren et al 2009), phospho-S5 Pol II (GSM588577) (Joseph et al 2010), H3K4me3 (GSM945269), H3K4me2 (GSM822391) (He et al 2012), H3K9ac (GSM588573) (Joseph et al 2010), H3K9me1 (GSM945857), H3K14ac (GSM588575) (Joseph et al 2010), H3K27ac (GSM946850) (Frietze et al 2012), MYC (GSM1006877), and RAD21 (GSM101079); MeDIP-seq (DRX000030) (Ruike et al 2010); and GRO-seq (GSM1014637) (Hah et al 2011). For IMR90 cells, the following data set was used: GRO-seq (GSM340901) (Core et al 2008).…”