H3K4Me3

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Yang Shi - One of the best experts on this subject based on the ideXlab platform.

  • suppression of enhancer overactivation by a rack7 histone demethylase complex
    Cell, 2016
    Co-Authors: Hongjie Shen, Yujiang Geno Shi, Rui Guo, Bowen Rong, Zhentian Wang, Lijuan Zheng, Zhi Ming Shao, Pengyuan Yang, Yang Shi
    Abstract:

    Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4Me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4Me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4Me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.

  • atrx add domain links an atypical histone methylation recognition mechanism to human mental retardation syndrome
    Nature Structural & Molecular Biology, 2011
    Co-Authors: Shigeki Iwase, Dinshaw J Patel, David C Allis, Bin Xiang, Sharmistha Ghosh, Ting Ren, Peter W Lewis, Jesse C Cochrane, David J Picketts, Yang Shi
    Abstract:

    ATR-X syndrome is a congenital disease linked to mutations in ATRX. The ADD domain in ATRX is now found to form a new histone H3 recognition module with binding being promoted by H3K9me3 and antagonized by H4K4me3. Co-crystal structures indicated that H3K9me3 is bound in a polar pocket formed between a GATA-like and PHD domain. Loss of this binding leads to ATRX mislocalization in vivo and has been linked to ATR-X syndrome.

  • the x linked mental retardation gene smcx jarid1c defines a family of histone h3 lysine 4 demethylases
    Cell, 2007
    Co-Authors: Shigeki Iwase, Pete E Ayliss, Luis De La Torreubieta, Maite Huarte, Johnatha R Whetstine, Azad Onni, Thomas M Roberts, Yang Shi
    Abstract:

    Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4Me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4Me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4Me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4Me3 demethylases and uncover a critical link between histone modifications and XLMR.

Shigeki Iwase - One of the best experts on this subject based on the ideXlab platform.

  • a mouse model of x linked intellectual disability associated with impaired removal of histone methylation
    Cell Reports, 2016
    Co-Authors: Aimee I. Badeaux, Emily Brookes, Shigeki Iwase, Saurabh Agarwal, Hikaru Ito, Christina N Vallianatos, Giulio Srubek Tomassy, Tomas Kasza, Grace Lin
    Abstract:

    Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4Me3, where it fine-tunes H3K4Me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes.

  • atrx add domain links an atypical histone methylation recognition mechanism to human mental retardation syndrome
    Nature Structural & Molecular Biology, 2011
    Co-Authors: Shigeki Iwase, Dinshaw J Patel, David C Allis, Bin Xiang, Sharmistha Ghosh, Ting Ren, Peter W Lewis, Jesse C Cochrane, David J Picketts, Yang Shi
    Abstract:

    ATR-X syndrome is a congenital disease linked to mutations in ATRX. The ADD domain in ATRX is now found to form a new histone H3 recognition module with binding being promoted by H3K9me3 and antagonized by H4K4me3. Co-crystal structures indicated that H3K9me3 is bound in a polar pocket formed between a GATA-like and PHD domain. Loss of this binding leads to ATRX mislocalization in vivo and has been linked to ATR-X syndrome.

  • the x linked mental retardation gene smcx jarid1c defines a family of histone h3 lysine 4 demethylases
    Cell, 2007
    Co-Authors: Shigeki Iwase, Pete E Ayliss, Luis De La Torreubieta, Maite Huarte, Johnatha R Whetstine, Azad Onni, Thomas M Roberts, Yang Shi
    Abstract:

    Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4Me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4Me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4Me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4Me3 demethylases and uncover a critical link between histone modifications and XLMR.

Haitao Li - One of the best experts on this subject based on the ideXlab platform.

  • multifaceted histone h3 methylation and phosphorylation readout by the plant homeodomain finger of human nuclear antigen sp100c
    Journal of Biological Chemistry, 2016
    Co-Authors: Xiaojie Zhang, Dan Zhao, Xiaozhe Xiong, Zhimin He, Haitao Li
    Abstract:

    The decoding of histone post-translational modifications by chromatin-binding modules ("readers") constitutes one major mechanism of epigenetic regulation. Nuclear antigen Sp100 (SPECKLED, 100 kDa), a constitutive component of the promyelocytic leukemia nuclear bodies, plays key roles in intrinsic immunity and transcriptional repression. Sp100C, a splicing isoform specifically up-regulated upon interferon stimulation, harbors a unique tandem plant homeodomain (PHD) finger and bromodomain at its C terminus. Combining structural, quantitative binding, and cellular co-localization studies, we characterized Sp100C PHD finger as an unmethylated histone H3 Lys(4) (H3K4me0) reader that tolerates histone H3 Thr(3) phosphorylation (H3T3ph), histone H3 Lys(9) trimethylation (H3K9me3), and histone H3 Ser(10) phosphorylation (H3S10ph), hallmarks associated with the mitotic chromosome. In contrast, whereas H3K4me0 reader activity is conserved in Sp140, an Sp100C paralog, the multivalent tolerance of H3T3ph, H3K9me3, and H3S10ph was lost for Sp140. The complex structure determined at 2.1 A revealed a highly coordinated lysine ϵ-amine recognition sphere formed by an extended N-terminal motif for H3K4me0 readout. Interestingly, reader pocket rigidification by disulfide bond formation enhanced H3K4me0 binding by Sp100C. An additional complex structure solved at 2.7 A revealed that H3T3ph is recognized by the arginine residue, Arg(713), that is unique to the PHD finger of Sp100C. Consistent with a restrictive cellular role of Sp100C, these results establish a direct chromatin targeting function of Sp100C that may regulate transcriptional gene silencing and promyelocytic leukemia nuclear body-mediated intrinsic immunity in response to interferon stimulation.

Chunhsi Huang - One of the best experts on this subject based on the ideXlab platform.

  • gene expression and gene ontology enrichment analysis for H3K4Me3 and h3k4me1 in mouse liver and mouse embryonic stem cell using chip seq and rna seq
    Gene regulation and systems biology, 2014
    Co-Authors: Ngoc Tam L Tran, Chunhsi Huang
    Abstract:

    Recent study has identified the cis-regulatory elements in the mouse genome as well as their genomic localizations. Recent discoveries have shown the enrichment of H3 lysine 4 trimethylation (H3K4Me3) binding as an active promoter and the presence of H3 lysine 4 monomethylation (H3K4me1) outside promoter regions as a mark for an enhancer. In this work, we further identified highly expressed genes by H3K4Me3 mark or by both H3K4Me3 and H3K4me1 marks in mouse liver using ChIP-Seq and RNA-Seq. We found that in mice, the liver carries embryonic stem cell-related functions while the embryonic stem cell also carries liver-related functions. We also identified novel genes in RNA-Seq experiments for mouse liver and for mouse embryonic stem cells. These genes are not currently in the Ensemble gene database at NCBI.

Xiaohong Lei - One of the best experts on this subject based on the ideXlab platform.

  • Alterations of Epigenetic Signatures in Hepatocyte Nuclear Factor 4a Deficient Mouse Liver Determined by Improved ChIP-qPCR and (h)MeDIP-qPCR Assays
    2014
    Co-Authors: Qinghao Zhang, Xiaohong Lei
    Abstract:

    Hepatocyte nuclear factor 4a (HNF4a) is a liver-enriched transcription factor essential for liver development and function. In hepatocytes, HNF4a regulates a large number of genes important for nutrient/xenobiotic metabolism and cell differentiation and proliferation. Currently, little is known about the epigenetic mechanism of gene regulation by HNF4a. In this study, the global and specific alterations at the selected gene loci of representative histone modifications and DNA methylations were investigated in Hnf4a-deficient female mouse livers using the improved MeDIP-, hMeDIP- and ChIP-qPCR assay. Hnf4a deficiency significantly increased hepatic total IPed DNA fragments for histone H3 lysine-4 dimethylation (H3K4me2), H3K4Me3, H3K9me2, H3K27me3 and H3K4 acetylation, but not for H3K9me3, 5-methylcytosine,or 5-hydroxymethylcytosine. At specific gene loci, the relative enrichments of histone and DNA modifications were changed to different degree in Hnf4a-deficient mouse liver. Among the epigenetic signatures investigated, changes in H3K4Me3 correlated the best with mRNA expression. Additionally, Hnf4a-deficient livers had increased mRNA expression of histone H1.2 and H3.3 as well as epigenetic modifiers Dnmt1, Tet3, Setd7, Kmt2c, Ehmt2, and Ezh2. In conclusion, the present study provides convenient improved (h)MeDIP- and ChIP-qPCR assays for epigenetic study. Hnf4a deficiency in young-adult mouse liver markedly alters histone methylation and acetylation, with fewer effects on DNA methylation and 5-hydroxymethylation. The underlying mechanism may be the induction of epigenetic enzymes responsible for the addition

  • Alterations of Epigenetic Signatures in Hepatocyte Nuclear Factor 4α Deficient Mouse Liver Determined by Improved ChIP-qPCR and (h)MeDIP-qPCR Assays
    2014
    Co-Authors: Qinghao Zhang, Xiaohong Lei
    Abstract:

    Hepatocyte nuclear factor 4α (HNF4α) is a liver-enriched transcription factor essential for liver development and function. In hepatocytes, HNF4α regulates a large number of genes important for nutrient/xenobiotic metabolism and cell differentiation and proliferation. Currently, little is known about the epigenetic mechanism of gene regulation by HNF4α. In this study, the global and specific alterations at the selected gene loci of representative histone modifications and DNA methylations were investigated in Hnf4a-deficient female mouse livers using the improved MeDIP-, hMeDIP- and ChIP-qPCR assay. Hnf4a deficiency significantly increased hepatic total IPed DNA fragments for histone H3 lysine-4 dimethylation (H3K4me2), H3K4Me3, H3K9me2, H3K27me3 and H3K4 acetylation, but not for H3K9me3, 5-methylcytosine,or 5-hydroxymethylcytosine. At specific gene loci, the relative enrichments of histone and DNA modifications were changed to different degree in Hnf4a-deficient mouse liver. Among the epigenetic signatures investigated, changes in H3K4Me3 correlated the best with mRNA expression. Additionally, Hnf4a-deficient livers had increased mRNA expression of histone H1.2 and H3.3 as well as epigenetic modifiers Dnmt1, Tet3, Setd7, Kmt2c, Ehmt2, and Ezh2. In conclusion, the present study provides convenient improved (h)MeDIP- and ChIP-qPCR assays for epigenetic study. Hnf4a deficiency in young-adult mouse liver markedly alters histone methylation and acetylation, with fewer effects on DNA methylation and 5-hydroxymethylation. The underlying mechanism may be the induction of epigenetic enzymes responsible for the addition/removal of the epigenetic signatures, and/or the loss of HNF4αper se as a key coordinator for epigenetic modifiers.