Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
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Contributed by William G. Kaelin, Jr., September 27, 2012 (sent for review August 10, 2012)
Abstract
Epigenetic regulation underlies the robust changes in gene expression that occur during development. How precisely epigenetic enzymes contribute to development and differentiation processes is largely unclear. Here we show that one of the enzymes that removes the activating epigenetic mark of trimethylated lysine 4 on histone H3, lysine (K)-specific demethylase 5A (KDM5A), reinforces the effects of the retinoblastoma (RB) family of transcriptional repressors on differentiation. Global location analysis showed that KDM5A cooccupies a substantial portion of target genes with the E2F4 transcription factor. During ES cell differentiation, knockout of KDM5A resulted in derepression of multiple genomic loci that are targets of KDM5A, denoting a direct regulatory function. In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB-related protein p130, a DREAM complex component. KDM5A was recruited to the transcription start site regions independently of E2F4; however, it cooperated with E2F4 to promote a state of deepened repression at cell cycle genes during differentiation. These findings reveal a critical role of H3K4 demethylation by KDM5A in the transcriptional silencing of genes that are suppressed by RB family members in differentiated cells.
Footnotes
↵1M.L.B. and K.B.H. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: william_kaelin{at}dfci.harvard.edu or evb{at}uic.edu.
Author contributions: W.G.K. and E.V.B. designed research; M.L.B., K.B.H., W.F.R., S.H., and E.V.B. performed research; M.L.B., K.B.H., Q.Y., L.P., N.G., W.G.K., and E.V.B. contributed new reagents/analytic tools; M.L.B., K.B.H., A.B.M.M.K.I., L.L., N.L.-B., and E.V.B. analyzed data; and M.L.B., W.G.K., and E.V.B. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE28343).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1216724109/-/DCSupplemental.
Control of cell cycle genes by KDM5A and E2F4
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