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PMID:20622853

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Citation

Qi, HH, Sarkissian, M, Hu, GQ, Wang, Z, Bhattacharjee, A, Gordon, DB, Gonzales, M, Lan, F, Ongusaha, PP, Huarte, M, Yaghi, NK, Lim, H, Garcia, BA, Brizuela, L, Zhao, K, Roberts, TM and Shi, Y (2010) Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 466:503-7

Abstract

X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.

Links

PubMed PMC3072215 Online version:10.1038/nature09261

Keywords

Animals; Biocatalysis; Brain/cytology; Brain/embryology; Brain/enzymology; Catalytic Domain; Cell Cycle; Cell Line, Tumor; Cell Survival; DNA, Intergenic/genetics; Gene Expression Regulation; Head/embryology; Histone Demethylases/genetics; Histone Demethylases/metabolism; Histones/chemistry; Histones/metabolism; Homeodomain Proteins/genetics; Humans; Jaw/cytology; Jaw/embryology; Lysine/metabolism; Mental Retardation, X-Linked/enzymology; Mental Retardation, X-Linked/genetics; Methylation; Neurons/cytology; Neurons/enzymology; Promoter Regions, Genetic; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription Initiation Site; Zebrafish/embryology; Zebrafish/metabolism; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:PHF8

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0043523: regulation of neuron apoptotic process

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-GENE-980526-26,ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0048703: embryonic viscerocranium morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-GENE-980526-26

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0048703: embryonic viscerocranium morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0048703: embryonic viscerocranium morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

DANRE:PHF8

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

DANRE:MSXB

involved_in

GO:0043523: regulation of neuron apoptotic process

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

DANRE:MSXB

involved_in

GO:0048703: embryonic viscerocranium morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100802-1

P

Seeded From UniProt

complete

HUMAN:KDM7A

enables

GO:0035575: histone H4-methyl-lysine-20 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM7A

involved_in

GO:0070544: histone H3-K36 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM7A

involved_in

GO:0071557: histone H3-K27 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM7A

involved_in

GO:0033169: histone H3-K9 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM7A

involved_in

GO:0035574: histone H4-K20 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM7A

enables

GO:0032454: histone H3-methyl-lysine-9 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM7A

enables

GO:0051864: histone H3-methyl-lysine-36 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM7A

enables

GO:0071558: histone H3-tri/di-methyl-lysine-27 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PHF8

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PHF8

enables

GO:0035064: methylated histone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PHF8

enables

GO:0035575: histone H4-methyl-lysine-20 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PHF8

involved_in

GO:0070544: histone H3-K36 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PHF8

involved_in

GO:0071557: histone H3-K27 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PHF8

involved_in

GO:0033169: histone H3-K9 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PHF8

involved_in

GO:0035574: histone H4-K20 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PHF8

enables

GO:0032454: histone H3-methyl-lysine-9 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PHF8

enables

GO:0051864: histone H3-methyl-lysine-36 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PHF8

enables

GO:0071558: histone H3-tri/di-methyl-lysine-27 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:LMBL1

enables

GO:0035064: methylated histone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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