title: Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2.
abstract: Cell differentiation requires remodeling of tissue-specific gene loci and activities of key transcriptional regulators, which are recognized for their dominant control over cellular programs. Using epigenomic methods, we characterized enhancer elements specifically modified in differentiating intestinal epithelial cells and found enrichment of transcription factor-binding motifs corresponding to CDX2, a critical regulator of the intestine. Directed investigation revealed surprising lability in CDX2 occupancy of the genome, with redistribution from hundreds of sites occupied only in proliferating cells to thousands of new sites in differentiated cells. Knockout mice confirmed distinct Cdx2 requirements in dividing and mature adult intestinal cells, including responsibility for the active enhancer configuration associated with maturity. Dynamic CDX2 occupancy corresponds with condition-specific gene expression and, importantly, to differential co-occupancy with other tissue-restricted transcription factors, such as GATA6 and HNF4A. These results reveal dynamic, context-specific functions and mechanisms of a prominent transcriptional regulator within a cell lineage.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Verzi
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Shin
authors.forename: H Hansen
authors.initials: HH
authors.lastname: He
authors.forename: Rita
authors.initials: R
authors.lastname: Sulahian
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Meyer
authors.forename: Robert K
authors.initials: RK
authors.lastname: Montgomery
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
mesh_terms: D000818:Animals; D001483:Base Sequence; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D057890:Epigenomics / Q000379:methods; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071616:CDX2 Transcription Factor; D002843:Chromatin; D050993:GATA6 Transcription Factor; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D018398:Homeodomain Proteins; D015534:Trans-Activators; D014157:Transcription Factors