Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells
- Mark M.W. Chong1,3,
- Natalie Simpson1,
- Maria Ciofani1,
- Grace Chen1,
- Amélie Collins1 and
- Dan R. Littman1,2,4
- 1The Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA;
- 2Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
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 (E4P) 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. “Active” histone modifications, once initiated by E4P, were also propagated independently of the enhancer. Thus, E4P 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.
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Footnotes
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↵4 Corresponding author.
E-MAIL dan.littman{at}med.nyu.edu; FAX (212) 263-1498.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1901610.
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Supplemental material is available at http://www.genesdev.org.
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- Received January 4, 2010.
- Accepted February 23, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press