Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat-containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes. PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3. A point mutation within the JmjC domain that is linked to mental retardation with cleft lip and palate (XLMR-CL/P) abolishes demethylase activity and transcriptional activation. Though further work is needed to unravel the contribution of PHF8 activity to mental retardation and cleft lip/palate, our results reveal a functional interplay between H3K4 methylation and H3K9me1/2 demethylation, linking dynamic histone methylation to rDNA transcription and neural disease.
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PMID:PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. 2020 42

Mental retardation (MR) is a highly diverse group of cognitive disorders. Gene defects account for about half of all patients and mutations causative for impaired cognition have been identified in more than 400 genes. While there are numerous genetic defects underlying MR, a more limited number of pathways is emerging whose disruption appears to be shared by groups of MR genes. One of these common pathways is composed of MR genes that encode regulators of chromatin structure and of chromatin-mediated transcription regulation. Already more than 20 "epigenetic MR genes" have been identified and this number is likely to increase in the coming years when deep sequencing of exomes and genomes will become commonplace. Prominent examples of epigenetic MR genes include the methyl CpG-binding protein MECP2 and the CREB binding protein, CBP. Interestingly, several epigenetic MR proteins have been found to interact directly with one another or act together in complexes that regulate the local chromatin structure at target genes. Thus, it appears that the functions of individual epigenetic MR proteins converge onto similar biological processes that are crucial to neuronal processes. The next challenge will be to gain more insight into patterns of altered DNA methylation and histone modifications that are caused by epigenetic gene mutations and how these will disrupt the brain-specific expression of target genes. Such research may reveal that a wide variety of mutations in the genetic code result in a more limited number of disruptions to the epigenetic code. If so, this will provide a rationale for therapeutic strategies.
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PMID:Disruption of the epigenetic code: an emerging mechanism in mental retardation. 2030 68

Immunodeficiency, Centromeric region instability, Facial anomalies (ICF; OMIM #242860) syndrome, due to mutations in the DNMT3B gene, is characterized by inheritance of aberrant patterns of DNA methylation and heterochromatin defects. Patients show variable agammaglobulinemia and a reduced number of T cells, making them prone to infections and death before adulthood. Other variable symptoms include facial dysmorphism, growth and mental retardation. Despite the recent advances in identifying the dysregulated genes, the molecular mechanisms, which underlie the altered gene expression causing ICF phenotype complexity, are not well understood. Held the recently-shown tight correlation between epigenetics and microRNAs (miRNAs), we searched for miRNAs regulated by DNMT3B activity, comparing cell lines from ICF patients with those from healthy individuals. We observe that eighty-nine miRNAs, some of which involved in immune function, development and neurogenesis, are dysregulated in ICF (LCLs) compared to wild-type cells. Significant DNA hypomethylation of miRNA CpG islands was not observed in cases of miRNA up-regulation in ICF cells, suggesting a more subtle effect of DNMT3B deficiency on their regulation; however, a modification of histone marks, especially H3K27 and H3K4 trimethylation, and H4 acetylation, was observed concomitantly with changes in microRNA expression. Functional correlation between miRNA and mRNA expression of their targets allow us to suppose a regulation either at mRNA level or at protein level. These results provide a better understanding of how DNA methylation and histone code interact to regulate the class of microRNA genes and enable us to predict molecular events possibly contributing to ICF condition.
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PMID:Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome. 2044 64

Fragile X syndrome (FXS) is the leading cause of inherited mental retardation, due to expansion and methylation of the CGG sequence at the 5' UTR of the FMR1 gene. Around 90% of affected boys present with attention deficit hyperactivity disorder (ADHD), while this percentage is lower in FXS girls (35-47%). Treatment of these behavioral symptoms is critical for many families. In an attempt at identifying drugs capable of restoring the activity of the FMR1 gene, we investigated the use of valproic acid (VPA), a well-known antiepileptic drug, also used as a mood stabilizer and in migraine therapy. It is described as an inhibitor of histone deacetylase (HDAC) and, possibly, as a DNA demethylating agent. In an in vitro study we observed that treatment of lymphoblastoid cells from FXS patients with VPA caused a modest reactivation of FMR1 transcription and increased levels of histone acetylation, confirming the histone hyperacetylating effect, but not its putative DNA demethylating activity. On the basis of these findings, we decided to evaluate the in vivo efficacy of VPA on ADHD symptoms in FXS patients. We observed an improvement in the adaptive behavior, defined as the performance of daily activities required for personal and social competence, due to a significant reduction in hyperactivity after VPA treatment. This treatment could be considered as an alternative to that with stimulants, whose efficacy in patients with FXS needs to be confirmed by further studies.
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PMID:Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys. 2073 28

The histone variant H3.3 marks active chromatin by replacing the conventional histone H3.1. In this study, we investigate the detailed mechanism of H3.3 replication-independent deposition. We found that the death domain-associated protein DAXX and the chromatin remodeling factor ATRX (alpha-thalassemia/mental retardation syndrome protein) are specifically associated with the H3.3 deposition machinery. Bacterially expressed DAXX has a marked binding preference for H3.3 and assists the deposition of (H3.3-H4)(2) tetramers on naked DNA, thus showing that DAXX is a H3.3 histone chaperone. In DAXX-depleted cells, a fraction of H3.3 was found associated with the replication-dependent machinery of deposition, suggesting that cells adapt to the depletion. The reintroduced DAXX in these cells colocalizes with H3.3 into the promyelocytic leukemia protein (PML) bodies. Moreover, DAXX associates with pericentric DNA repeats, and modulates the transcription from these repeats through assembly of H3.3 nucleosomes. These findings establish a new link between the PML bodies and the regulation of pericentric DNA repeat chromatin structure. Taken together, our data demonstrate that DAXX functions as a bona fide histone chaperone involved in the replication-independent deposition of H3.3.
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PMID:The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. 2059 28

Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation (XLMR) and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor (RAR). Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellular-based assays, recombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 (phenylalanine at position 279 to serine) identified in the XLMR patients is defective in enzymatic activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives P19 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RARalpha and functions as a coactivator for RARalpha. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.
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PMID:The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. 2054 36

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.
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PMID:Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. 2062 53

The histone variant H3.3 is implicated in the formation and maintenance of specialized chromatin structure in metazoan cells. H3.3-containing nucleosomes are assembled in a replication-independent manner by means of dedicated chaperone proteins. We previously identified the death domain associated protein (Daxx) and the alpha-thalassemia X-linked mental retardation protein (ATRX) as H3.3-associated proteins. Here, we report that the highly conserved N terminus of Daxx interacts directly with variant-specific residues in the H3.3 core. Recombinant Daxx assembles H3.3/H4 tetramers on DNA templates, and the ATRX-Daxx complex catalyzes the deposition and remodeling of H3.3-containing nucleosomes. We find that the ATRX-Daxx complex is bound to telomeric chromatin, and that both components of this complex are required for H3.3 deposition at telomeres in murine embryonic stem cells (ESCs). These data demonstrate that Daxx functions as an H3.3-specific chaperone and facilitates the deposition of H3.3 at heterochromatin loci in the context of the ATRX-Daxx complex.
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PMID:Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. 2065 Dec 53

Epigenetic chromatin remodeling, including reversible histone methylation, regulates gene transcription in brain development and synaptic plasticity. Aberrant chromatin modifications due to mutant chromatin enzymes or chemical exposures have been associated with neurological or psychiatric disorders such as mental retardation, schizophrenia, depression, and drug addiction. Some chromatin enzymes, such as histone demethylases JARID1C and UTX, are coded by X-linked genes which are not X-inactivated in females. The higher expression of JARID1C and UTX in females could contribute to sex differences in brain development and behavior.
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PMID:Reversible histone methylation regulates brain gene expression and behavior. 2081 65

Several recent publications demonstrate a co-activator function for a subgroup of plant homeodomain fingers, which in humans comprises PHF2, PHF8 and KIAA1718. Besides an N-terminal plant homeodomain (PHD) these proteins also harbor an enzymatically active Jumonji-C domain (JmjC). While they have been shown to bind via their PHDs to H3K4me3-bearing nucleosomes at active gene promoters, their JmjC-domains are able to remove mono- and dimethyl-lysine 9 or 27 on histone H3, and monomethyl-lysine 20 on histone H4, chromatin modifications which correlate with transcriptional repression. Such dual histone crosstalk insures the proper removal of repressive histone marks following transcriptional activation by RNA polymerases I and II. Mutations in the PHF8 gene lead to X-linked mental retardation (XLMR) and knockdown of KIAA1718 and PHF8 homologs in zebrafish causes brain defects. Thus, the co-activator function of this new class of chromatin modifying enzymes has important functional roles in neuronal development. To continue with the nomenclature for histone demethylases, we propose the usage of KDM7A, -B and -C for KIAA1718, PHF8 and PHF2 proteins, respectively.
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PMID:Plant homeodomain fingers form a helping hand for transcription. 2081 69


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