Topic
PHF8
About: PHF8 is a research topic. Over the lifetime, 19 publications have been published within this topic receiving 1592 citations. The topic is also known as: JHDM1F & MRXSSD.
Papers
TL;DR: 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.
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. PHF8 is a JmjC domain-containing protein, the gene for which has been linked to X-linked mental retardation (XLMR). These authors demonstrate PHF8 to be a histone demethylase with activity against H4K20me1. It has a role 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 XLMR. X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; 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 ∼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 pathways3. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
288 citations
TL;DR: In this article, the PHD finger protein 8 (PHF8) was found to be associated with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263).
Abstract: Truncating mutations were found in the PHF8 gene (encoding the PHD finger protein 8) in two unrelated families with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263). Expression studies showed that this gene is ubiquitously transcribed, with strong expression of the mouse orthologue Phf8 in embryonic and adult brain structures. The coded PHF8 protein harbours two functional domains, a PHD finger and a JmjC (Jumonji-like C terminus) domain, implicating it in transcriptional regulation and chromatin remodelling. The association of XLMR and cleft lip/palate in these patients with mutations in PHF8 suggests an important function of PHF8 in midline formation and in the development of cognitive abilities, and links this gene to XLMR associated with cleft lip/palate. Further studies will explore the specific mechanisms whereby PHF8 alterations lead to mental retardation and midline defects.
232 citations
TL;DR: PHF8 is a histone demethylase that removes repressive histone H3 dimethyl lysine 9 marks and is the first demonstration of a chromatin-modifying enzyme that is globally recruited to promoters through its association with H3K4me3 and RNAPII.
Abstract: Mutations in PHF8 are associated with X-linked mental retardation and cleft lip/cleft palate PHF8 contains a plant homeodomain (PHD) in its N terminus and is a member of a family of JmjC domain-containing proteins While PHDs can act as methyl lysine recognition motifs, JmjC domains can catalyze lysine demethylation Here, we show that PHF8 is a histone demethylase that removes repressive histone H3 dimethyl lysine 9 marks Our biochemical analysis revealed specific association of the PHF8 PHD with histone H3 trimethylated at lysine 4 (H3K4me3) Chromatin immunoprecipitation followed by high-throughput sequencing indicated that PHF8 is enriched at the transcription start sites of many active or poised genes, mirroring the presence of RNA polymerase II (RNAPII) and of H3K4me3-bearing nucleosomes We show that PHF8 can act as a transcriptional coactivator and that its activation function largely depends on binding of the PHD to H3K4me3 Furthermore, we present evidence for direct interaction of PHF8 with the C-terminal domain of RNAPII Importantly, a PHF8 disease mutant was defective in demethylation and in coactivation This is the first demonstration of a chromatin-modifying enzyme that is globally recruited to promoters through its association with H3K4me3 and RNAPII
117 citations
TL;DR: A novel nonsense mutation is reported in a male patient who has MR associated with CL/P, which results in a truncated PHF8 protein lacking the Jumonji‐like C terminus domain and five nuclear localization signals, which supports the hypothesis that the PHf8 protein may play an important role in cognitive function and midline formation.
Abstract: Recently, two truncating mutations in the PHF8 (plant homeodomain finger protein 8) gene have been found to cause X-linked mental retardation associated with cleft lip/cleft palate (CL/P). One of the truncating mutations was found in the original family with Siderius–Hamel CL/P syndrome where only two of the three affected individuals had mental retardation (MR) with CL/P and one individual had mild MR. The second mutation was present in a family with four affected men, three of whom had MR and CL/P, while the fourth individual had mild MR without clefting. Here, we report a novel nonsense mutation (p.K177X) in a male patient who has MR associated with CL/P. The mutation results in a truncated PHF8 protein lacking the Jumonji-like C terminus domain and five nuclear localization signals. Our finding further supports the hypothesis that the PHF8 protein may play an important role in cognitive function and midline formation.
102 citations
TL;DR: A novel missense mutation c.836C>T of the PHF8 gene was identified in a Finnish family with multiple‐affected male patients and changes phenylalanine to serine (F279S) in the functionally important Jmonji C domain of the protein.
Abstract: We investigated the prevalence of mutations in the PHD finger protein 8 (PHF8) gene in X-linked mental retardation (XLMR) and facial cleft starting from the original cohort of 7712 patients operated on since 1 January 1950 for cleft lip/cleft palate in the Cleft Centre at the Helsinki University Hospital. From this nationwide material, 18 patients including one family with two male patients with cleft lip/cleft palate and unknown cause of mental retardation (MR) were sequenced for the coding regions and splice sites of the PHF8 gene. A novel missense mutation c.836C>T of the PHF8 gene was identified in a Finnish family with multiple-affected male patients. The mutation resides in exon 8 and changes phenylalanine to serine (F279S) in the functionally important Jmonji C domain of the protein. The clinical phenotype of the male patients was characterized by mild MR, mild dysmorphic features, unilateral cleft lip and cleft palate in one and bilateral cleft lip and cleft palate in the other sibling. The mutation was not present in 200 anonymous blood donors (approximately 300 X-chromosomes). To our knowledge, F279S is the third mutation of the PHF8 gene identified so far.
93 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2018 | 2 |
| 2017 | 1 |
| 2014 | 1 |
| 2010 | 9 |
| 2008 | 1 |