Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells

Mark M.W. Chong, Natalie Simpson, Maria Ciofani, Grace Chen, Amélie Collins, Dan R. Littman

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

The stability of a lineage program (cellular memory) is dependent on mechanisms that epigenetically maintain active or repressed states of gene expression (transcriptional memory). Although epigenetic silencing of genes has been clearly demonstrated from yeast to mammals, heritable maintenance of active transcription has been less clearly defined. To investigate the potential role of active transcriptional memory during lineage diversification, we employed targeted mutation of a positive-acting cis element in the Cd4 locus to determine the impact on CD4 expression and the differentiation of CD4+ helper T cells in mice. We show that the proximal enhancer [Mp) of Cd4 is essential for CD4 expression in immature CD4+8+ thymocytes. Futhermore, its loss resulted in reduced and unstable expression of CD4 in mature T cells. However, if the enhancer was deleted after cells had already committed to the helper T-cell lineage, CD4 expression remained high and was stable upon cell division. quot;Activequot; histone modifications, once initiated by E4 p were also propagated independently of the enhancer. Thus, E4 P is responsible for establishing an epigenetically inherited active Cd4 locus in the helper T-cell lineage. To our knowledge, this is the first genetic demonstration of active transcriptional memory in mammalian cells.

Original languageEnglish
Pages (from-to)659-669
Number of pages11
JournalGenes and Development
Volume24
Issue number7
DOIs
StatePublished - 1 Apr 2010
Externally publishedYes

Keywords

  • CD4
  • Chromatin
  • Epigenetics
  • Gene regulation
  • T-cell development
  • Transcription

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