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Nan Liu Zhuqiang Zhang Hui Wu Yonghua Jiang Lingjun Meng Jun Xiong Zuodong Zhao Xiaohua Zhou Jia Li Hong Li Yong Zheng She Chen Tao Cai Shaorong Gao Bing Zhu 《Genes & development》2015,29(4):379-393
GLP and G9a are major H3K9 dimethylases and are essential for mouse early embryonic development. GLP and G9a both harbor ankyrin repeat domains that are capable of binding H3K9 methylation. However, the functional significance of their recognition of H3K9 methylation is unknown. Here, we report that the histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes that are premethylated at H3K9. These stimulation events function in cis and are dependent on the H3K9 methylation binding activities of ankyrin repeat domains of GLP and G9a. Disruption of the H3K9 methylation-binding activity of GLP in mice causes growth retardation of embryos, ossification defects of calvaria, and postnatal lethality due to starvation of the pups. In mouse embryonic stem cells (ESCs) harboring a mutant GLP that lacks H3K9me1-binding activity, critical pluripotent genes, including Oct4 and Nanog, display inefficient establishment of H3K9me2 and delayed gene silencing during differentiation. Collectively, our study reveals a new activation mechanism for GLP and G9a that plays an important role in ESC differentiation and mouse viability. 相似文献
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G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment
Xiaoji Chen Kyobi Skutt-Kakaria Jerry Davison Yang-Li Ou Edward Choi Punam Malik Keith Loeb Brent Wood George Georges Beverly Torok-Storb Patrick J. Paddison 《Genes & development》2012,26(22):2499-2511
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Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication 总被引:5,自引:1,他引:4
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Estève PO Chin HG Smallwood A Feehery GR Gangisetty O Karpf AR Carey MF Pradhan S 《Genes & development》2006,20(22):3089-3103
Chromatin methylation is necessary for stable repression of gene expression during mammalian development. During cell division, DNMT1 maintains the DNA methylation pattern of the newly synthesized daughter strand, while G9a methylates H3K9. Here, DNMT1 is shown to directly bind G9a both in vivo and in vitro and to colocalize in the nucleus during DNA replication. The complex of DNMT1 and G9a colocalizes with dimethylated H3K9 (H3K9me2) at replication foci. Similarly, another H3K9 histone methyltransferase, SUV39H1, colocalizes with DNMT1 on heterochromatic regions of the nucleoli exclusively before cell division. Both DNMT1 and G9a are loaded onto the chromatin simultaneously in a ternary complex with loading factor PCNA during chromatin replication. Small interfering RNA (siRNA) knockdown of DNMT1 impairs DNA methylation, G9a loading, and H3K9 methylation on chromatin and rDNA repeats, confirming DNMT1 as the primary loading factor. Additionally, the complex of DNMT1 and G9a led to enhanced DNA and histone methylation of in vitro assembled chromatin substrates. Thus, direct cooperation between DNMT1 and G9a provides a mechanism of coordinated DNA and H3K9 methylation during cell division. 相似文献
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The Polycomb Group Protein SUZ12 regulates histone H3 lysine 9 methylation and HP1α distribution 总被引:2,自引:0,他引:2
Cecile C. de la Cruz Antonis Kirmizis Matthew D. Simon Kyo-ichi Isono Haruhiko Koseki Barbara Panning 《Chromosome research》2007,15(3):299-314
Regulation of histone methylation is critical for proper gene expression and chromosome function. Suppressor of Zeste 12 (SUZ12)
is a requisite member of the EED/EZH2 histone methyltransferase complexes, and is required for full activity of these complexes
in vitro. In mammals and flies, SUZ12/Su(z)12 is necessary for trimethylation of histone H3 on lysine 27 (H3K27me3) on facultative
heterochromatin. However, Su(z)12 is unique among Polycomb Group Proteins in that Su(z)12 mutant flies exhibit gross defects in position effect variegation, suggesting a role for Su(z)12 in constitutive heterochromatin
formation. We investigated the role of Suz12 in constitutive heterochromatin and discovered that Suz12 is required for histone
H3 lysine 9 tri-methylation (H3K9me3) in differentiated but not undifferentiated mouse embryonic stem cells. Knockdown of
SUZ12 in human cells caused a reduction in H3K27me3 and H3K9me3, and altered the distribution of HP1α. In contrast, EZH2 knockdown
caused loss of H3K27me3 but not H3K9me3, indicating that SUZ12 regulates H3-K9 methylation in an EZH2-independent fashion.
This work uncovers a role for SUZ12 in H3-K9 methylation. 相似文献
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Comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, TFPI2/Tfpi2, which requires EHMT2 and EED for allelic-silencing
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Monk D Wagschal A Arnaud P Müller PS Parker-Katiraee L Bourc'his D Scherer SW Feil R Stanier P Moore GE 《Genome research》2008,18(8):1270-1281
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《Acta histochemica》2023,125(7):152073
ITGB3, an osteoclast marker, is involved in osteoclast formation. Nevertheless, its related mechanism remains poorly characterized. Herein, this study examines the mechanisms affecting osteoclast formation with the involvement of ITGB3. Osteoclast formation was induced with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL), followed by measurement of the mRNA and protein expression of ITGB3 and LSD1. After gain- and loss-of-function assays, cell viability and the expression of osteoclast marker genes (NFATc1, ACP5, and CTSK) were assessed, and osteoclast formation was evaluated with TRAP staining. ChIP assays were used to examine histone 3 lysine 9 (H3K9) monomethylation (H3K9me1) and H3K9 dimethylation (H3K9me2) modifications and LSD1 protein enrichment in the ITGB3 promoter. During osteoclast formation, ITGB3 and LSD1 were gradually augmented. Knockdown of LSD1 or ITGB3 curbed cell viability, the expression of osteoclast marker genes, and osteoclast formation. Moreover, overexpression of ITGB3 nullified the suppressive impact of LSD1 knockdown on osteoclast formation. Mechanistically, LSD1 promoted ITGB3 expression by reducing H3K9 levels in the ITGB3 promoter. LSD1 enhanced ITGB3 expression by decreasing H3K9me1 and H3K9me2 levels in ITGB3 promoter to boost osteoclast formation. 相似文献
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W.G. Sui H.Y. He Q. Yan J.J. Chen R.H. Zhang Y. Dai 《Brazilian journal of medical and biological research》2014,47(1):42-49
Membranous nephropathy (MN), characterized by the presence of diffuse thickening of
the glomerular basement membrane and subepithelial in situ immune
complex disposition, is the most common cause of idiopathic nephrotic syndrome in
adults, with an incidence of 5-10 per million per year. A number of studies have
confirmed the relevance of several experimental insights to the pathogenesis of human
MN, but the specific biomarkers of MN have not been fully elucidated. As a result,
our knowledge of the alterations in histone methylation in MN is unclear. We used
chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to
analyze the variations in a methylated histone (H3K9me3) in peripheral blood
mononuclear cells from 10 MN patients and 10 healthy subjects. There were 108 genes
with significantly different expression in the MN patients compared with the normal
controls. In MN patients, significantly increased activity was seen in 75 H3K9me3
genes, and decreased activity was seen in 33, compared with healthy subjects. Five
positive genes, DiGeorge syndrome critical region gene 6 (DGCR6), sorting nexin 16
(SNX16), contactin 4 (CNTN4), baculoviral IAP repeat containing 3 (BIRC3), and
baculoviral IAP repeat containing 2 (BIRC2), were selected and quantified. There were
alterations of H3K9me3 in MN patients. These may be candidates to help explain
pathogenesis in MN patients. Such novel findings show that H3K9me3 may be a potential
biomarker or promising target for epigenetic-based MN therapies. 相似文献
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马妮 《国际病理科学与临床杂志》2017,37(7)
常染色质组蛋白甲基化转移酶(euchromatin histone lysine methyltransferases,EHMTs)能够使基因组常染色质区域的组蛋白3第9位赖氨酸二甲基化(histone 39th lysine demethylate,H3K9-di).在哺乳动物中有两种EHMT基因编码蛋白,分别为EHMT1编码GLP和EHMT2编码G9a.EHMTs在不同组织和不同细胞分化的过程中扮演不同的角色并且参与到记忆、药物成瘾、免疫反应等成人特异性反应过程的形成.EHMTs及其蛋白在哺乳动物生殖过程中的配子发生、胚胎发育及子宫疾病等方面发挥重要的作用. 相似文献
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BackgroundsHistone methylation is recognized as an important component of the epigenetic mechanisms of cancer initiation and progression. Previous studies have demonstrated that aberrant alterations in histone methylation are associated with lung cancer. However, novel and specific epigenetic biomarkers for monitoring lung adenocarcinoma remain unknown.MethodsA retrospective clinicopathological analysis was performed on 71 lung adenocarcinoma (LUAD) patients who received complete ablative surgical treatment. Tissue arrays were made from the paraffin-embedded LUAD tumor tissues, and these, together with corresponding normal tissues, were examined through immunohistochemistry for several markers: histone 3 lysine 9 di-methylation (H3K9me2), histone 3 lysine 9 tri-methylation (H3K9me3), and histone 3 lysine 27 tri-methylation (H3K27me3). The expression level of each marker was analyzed according to the histological classification and clinical prognosis data.ResultsCompared with peri-cancerous tissues, cancerous tissues distinctly expressed higher proportions of H3K9me2, H3K9me3, and H3K27me3. A higher expression pattern of H3K27me3 was associated with the poorly differentiation and unfavorable prognosis in LUAD. Based on histological types, it was found that the H3K27me3 level of patients with micropapillary type is high, and it is related to worse prognosis.ConclusionsThe findings of this study show that the H3K27me3 and micropapillary type are malignant clinical factors of LUAD. H3K27me3 reduction is a novel epigenetic biomarker for defining high-risk LUAD and predicting worse prognosis. Immunohistochemical evaluation of H3K27me3 expression is an economic, easily available, and readily adaptable method. 相似文献
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目的 从治疗角度对组蛋白甲基化酶G9a在糖尿病足溃疡中的调控机制进行探索分析.方法 选取2型糖尿病足患者及对照受试者,取血液样本通过实时定量PCR测定组蛋白甲基化酶G9a以及H3K9me2表达水平;比较病情严重程度不同的两组疗效以及组蛋白甲基化酶G9a表达情况和疗效.SPSS17.0用于统计分析.结果 2型糖尿病足患者治疗后轻症组足溃疡面积减少30%及以上的比例高于重症组;轻症组治愈率和总有效率较高,无效率较低.治疗前轻症组及重症组患者组蛋白表达水平均低于对照组,但未见组间差别;同时H3K9me2在足溃疡患者中水平降低.治疗后两组患者与治疗前水平比较均有所提高,但仍低于对照组;且治疗后轻症足溃疡组的G9a表达、H3K9me2表达水平均高于重症患者.结论 组蛋白甲基化酶G9a可能参与糖尿病足溃疡的发生与发展,治疗干预可提高患者G9a表达,轻症患者增高更多. 相似文献
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Ji Zhang Yoshihiro Matsumura Yuka Kano Ayano Yoshida Takeshi Kawamura Hiroyuki Hirakawa Takeshi Inagaki Toshiya Tanaka Hiroshi Kimura Shigeru Yanagi Kiyoko Fukami Takefumi Doi Timothy F. Osborne Tatsuhiko Kodama Hiroyuki Aburatani Juro Sakai 《Genes to cells : devoted to molecular & cellular mechanisms》2021,26(7):513-529
The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity. 相似文献