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

Tissue-specific gene expression requires modulation of nucleosomes, allowing transcription factors to occupy cis elements that are accessible only in selected tissues. Master transcription factors control cell-specific genes and define cellular identities, but it is unclear if they possess special abilities to regulate cell-specific chromatin and if such abilities might underlie lineage determi-nation andmaintenance. One prevailing view is that several transcription factors enable chromatin access in combination. The homeodomain protein CDX2 specifies the embryonic intestinal epithelium, through unknownmechanisms, and partners with transcription factors such as HNF4A in the adult intestine. We examined enhancer chromatin and gene expression following Cdx2 orHnf4a excision in mouse intestines. HNF4A loss did not affect CDX2 binding or chromatin, whereas CDX2 depletion modified chromatin significantly at CDX2-bound enhancers, disrupted HNF4A occupancy, and abrogated expression of neigh-boring genes. Thus, CDX2maintains transcription-permissive chromatin, illustrating a powerful and dominant effect on en-hancer configuration in an adult tissue. Similar, hierarchical control of cell-specific chromatin states is probably a general prop-erty of master transcription factors. Cell identities and functions in multicellular organisms repre-sent the outcome of interactions between transcription fac-tors (TFs) and chromatin. Because nucleosomes restrict access of genomic DNA (1), TFs must overcome a steric barrier at the cis-regulatory elements of tissue-specific genes during developmen