PHF8

The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Full Name

PHF8

Function

Histone lysine demethylase with selectivity for the di- and monomethyl states that plays a key role cell cycle progression, rDNA transcription and brain development. Demethylates mono- and dimethylated histone H3 'Lys-9' residue (H3K9Me1 and H3K9Me2), dimethylated H3 'Lys-27' (H3K27Me2) and monomethylated histone H4 'Lys-20' residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Required for brain development, probably by regulating expression of neuron-specific genes. Only has activity toward H4K20Me1 when nucleosome is used as a substrate and when not histone octamer is used as substrate. May also have weak activity toward dimethylated H3 'Lys-36' (H3K36Me2), however, the relevance of this result remains unsure in vivo. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3.

Biological Process

Brain developmentISS:UniProtKB
Chromatin organizationIEA:UniProtKB-KW
G1/S transition of mitotic cell cycleManual Assertion Based On ExperimentIMP:UniProtKB
Histone H3-K27 demethylationManual Assertion Based On ExperimentIDA:UniProtKB
Histone H3-K36 demethylationManual Assertion Based On ExperimentIDA:UniProtKB
Histone H3-K9 demethylationManual Assertion Based On ExperimentIDA:UniProtKB
Histone H4-K20 demethylationManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of ribosomal DNA heterochromatin assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription by RNA polymerase IManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Protein demethylationManual Assertion Based On ExperimentIBA:GO_Central
Regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central

Cellular Location

Nucleus
Nucleus, nucleolus
Recruited to H3K4me3 sites on chromatin during interphase (PubMed:20622854).
Dissociates from chromatin when cells enter mitosis (PubMed:20622854).

Involvement in disease

Intellectual developmental disorder, X-linked, syndromic, Siderius type (MRXSSD):
A syndrome characterized by mild to borderline mental retardation with or without cleft lip/cleft palate.

PTM

Phosphorylation at Ser-69 and Ser-120 are required for dissociation from chromatin and accumulation of H4K20Me1 levels during prophase.