Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation.

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.

• Authors: Michael L Beshiri, Katherine B Holmes, William F Richter, Samuel Hess, Abul B M M K Islam, Qin Yan, Lydia Plante, Larisa Litovchick, Nicolas Gévry, Nuria Lopez-Bigas, William G Kaelin Jr, Elizaveta V Benevolenskaya
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 45 Pg. 18499-504 (Nov 06 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23093672 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• E2F4 Transcription Factor
• Histones
• Multiprotein Complexes
• Repressor Proteins
• KDM5A protein, human
• KDM5A protein, mouse
• Retinoblastoma-Binding Protein 2
• Lysine

Topics

• Animals
• Cell Differentiation (genetics)
• Chromatin Immunoprecipitation
• E2F4 Transcription Factor (metabolism)
• Embryonic Stem Cells (metabolism)
• Genes, cdc (genetics)
• Histones (metabolism)
• Humans
• Lysine (metabolism)
• Methylation
• Mice
• Mice, Inbred C57BL
• Multiprotein Complexes (metabolism)
• Protein Binding
• Repressor Proteins (metabolism)
• Retinoblastoma-Binding Protein 2 (metabolism)
• U937 Cells