TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis -regulatory regions

Abstract

Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genomewide analysis of DNA cis-regulatory regions bound by the intestinerestricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immunoprecipitation confirmed TCF4 occupancy at most such sites and cooccupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding. These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissuespecific outcomes.

DNA methylation is required for the control of stem cell differentiation in the small intestine

“…In coordination with these signaling pathways, transcription factors such as the Cdx proteins are required for expression of ISC genes, and genetic ablation of Cdx1 and Cdx2 causes total loss of the epithelium (Gao et al 2009;Gao and Kaestner 2010;Verzi et al 2011). Furthermore, in human intestinal Caco-2 cells, Cdx2 binding is associated with ISC genes in the undifferentiated state, and its binding profile overlaps with Tcf4, the major Wnt effector (Verzi et al 2010). Our DMRs show high overlap with the Cdx2 ChIP-seq binding profile (Verzi et al 2013).…”

Intestinal Master Transcription Factor CDX2 Controls Chromatin Access for Partner Transcription Factor Binding

“…CDX2 represents this class of master regulator TFs in the intestine because it induces an intestine-specific transcriptional program in heterologous stomach cells in vivo (15,49), specifies the developing intestine (14), and maintains adult intestinal integrity and function (16)(17)(18). Recent work highlights the additional activity of master regulator TFs in tailoring tissue-specific transcriptional programs in response to ubiquitous intercellular signals such as Wnt and transforming growth factor ␤ (TGF-␤) (12,13,50). Together, the powerful biological activities of lineage specification, cell maintenance, and cell-specific response suggest the possibility of a dominant role for such proteins within TF hierarchies.…”

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

“…However, little is known about the consequences of aberrant CDX2 expression in hematopoietic cells (12). Whereas the global gene expression patterns regulated by CDX2 have been determined in embryonic stem cells, intestinal cells, and human CRC cells (9,19,21,52,53), previous studies of murine and human AML were limited to selected HOX genes that are known transcriptional targets of CDX2 during development (14)(15)(16).…”

“…In support of this hypothesis, aberrant HOX gene programs have been observed in CDX2 + murine and human leukemias as well as in directly transduced HSPCs (14,15); however, more direct mechanistic evidence linking CDX2 to perturbed HOX gene expression in AML is currently lacking. Furthermore, Cdx2 is known to regulate a wide range of non-Hox genes during embryonic development and in the gastrointestinal tract (1,2,(18)(19)(20)(21). Therefore, it is likely that additional target genes of CDX2 contribute to its leukemogenic potential.…”