Essential and redundant functions of caudal family proteins in activating adult intestinal genes

Mol Cell Biol. 2011 May;31(10):2026-39. doi: 10.1128/MCB.01250-10. Epub 2011 Mar 14.

Abstract

Transcription factors that potently induce cell fate often remain expressed in the induced organ throughout life, but their requirements in adults are uncertain and varied. Mechanistically, it is unclear if they activate only tissue-specific genes or also directly repress heterologous genes. We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was significantly accelerated in mice lacking both Cdx2 and its homolog Cdx1, with particular exaggeration of defects in villus enterocyte differentiation. Importantly, Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a transcription factor's mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a critical developmental regulator that activates tissue-specific genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDX2 Transcription Factor
  • Cell Differentiation
  • Enterocytes / physiology*
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Intestinal Mucosa / embryology
  • Intestinal Mucosa / growth & development
  • Intestinal Mucosa / metabolism*
  • Mice
  • Mice, Knockout
  • Microarray Analysis
  • Molecular Sequence Data
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation*

Substances

  • CDX2 Transcription Factor
  • Cdx1 protein, mouse
  • Cdx2 protein, mouse
  • Homeodomain Proteins
  • Transcription Factors

Associated data

  • GEO/GSE24633