PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression
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Open Access
- 11 July 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 466 (7305), 508-512
- https://doi.org/10.1038/nature09272
Abstract
Mutations in the PHF8 gene, which encodes the plant homeo domain (PHD) finger protein 8, are connected to X-linked mental retardation associated with cleft lip and cleft palate. Two groups now report that the PHF8 protein is a histone demethylase with activity against H4K20me1 (histone H4 lysine 20). Qi et al. report a role for PHF8 in regulating gene expression, as well as in neuronal cell survival and craniofacial development in zebrafish. The results suggest there may be a link between histone methylation dynamics and X-linked mental retardation. Liu et al. show that PHF8 is linked to two distinct events during cell-cycle progression. PHF8 is recruited to the promoters of G1/S-phase genes where it removes H4K20me1 and contributes to gene activation, whereas dissociation of PHF8 from chromatin in prophase allows H4K20me1 to accumulate during mitosis. These authors show that the JmjC domain-containing protein PHF8 has histone demethylase activity against H4K20me1 and is linked to two distinct events during cell cycle progression. PHF8 is recruited to the promoters of genes involved in the G1–S phase transition, where it removes H4K20me1 and contributes to gene activation, whereas dissociation of PHF8 from chromatin in prophase allows H4K20me1 to accumulate during mitosis. While reversible histone modifications are linked to an ever-expanding range of biological functions1,2,3,4,5, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1–S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.Keywords
This publication has 43 references indexed in Scilit:
- A Functional Link between the Histone Demethylase PHF8 and the Transcription Factor ZNF711 in X-Linked Mental RetardationMolecular Cell, 2010
- Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylasesNature Structural & Molecular Biology, 2009
- Histone modifications at human enhancers reflect global cell-type-specific gene expressionNature, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic StabilityOnline Journal of Public Health Informatics, 2008
- Histone Methylation-Dependent Mechanisms Impose Ligand Dependency for Gene Activation by Nuclear ReceptorsCell, 2007
- [9] TM4 Microarray Software SuiteMethods in Enzymology, 2006
- Significance analysis of microarrays applied to the ionizing radiation responseProceedings of the National Academy of Sciences of the United States of America, 2001
- The language of covalent histone modificationsNature, 2000
- HEAT repeats in the Huntington's disease proteinNature Genetics, 1995