共查询到20条相似文献,搜索用时 919 毫秒
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LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription 总被引:4,自引:0,他引:4
Metzger E Wissmann M Yin N Müller JM Schneider R Peters AH Günther T Buettner R Schüle R 《Nature》2005,437(7057):436-439
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IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics 总被引:1,自引:0,他引:1
M Sasaki CB Knobbe JC Munger EF Lind D Brenner A Brüstle IS Harris R Holmes A Wakeham J Haight A You-Ten WY Li S Schalm SM Su C Virtanen G Reifenberger PS Ohashi DL Barber ME Figueroa A Melnick JC Zúñiga-Pflücker TW Mak 《Nature》2012,488(7413):656-659
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML. 相似文献
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UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development 总被引:2,自引:0,他引:2
Agger K Cloos PA Christensen J Pasini D Rose S Rappsilber J Issaeva I Canaani E Salcini AE Helin K 《Nature》2007,449(7163):731-734
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Meissner A Mikkelsen TS Gu H Wernig M Hanna J Sivachenko A Zhang X Bernstein BE Nusbaum C Jaffe DB Gnirke A Jaenisch R Lander ES 《Nature》2008,454(7205):766-770
DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine. 相似文献
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Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2 总被引:1,自引:0,他引:1
CA Doege K Inoue T Yamashita DB Rhee S Travis R Fujita P Guarnieri G Bhagat WB Vanti A Shih RL Levine S Nik EI Chen A Abeliovich 《Nature》2012,488(7413):652-655
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Barreto G Schäfer A Marhold J Stach D Swaminathan SK Handa V Döderlein G Maltry N Wu W Lyko F Niehrs C 《Nature》2007,445(7128):671-675
DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial. Here we show that Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes, Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks. 相似文献
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The Polycomb complex PRC2 and its mark in life 总被引:2,自引:0,他引:2
Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist - Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes. 相似文献
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p53 is regulated by the lysine demethylase LSD1 总被引:1,自引:0,他引:1
Huang J Sengupta R Espejo AB Lee MG Dorsey JA Richter M Opravil S Shiekhattar R Bedford MT Jenuwein T Berger SL 《Nature》2007,449(7158):105-108
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Role of histone H2A ubiquitination in Polycomb silencing 总被引:1,自引:0,他引:1
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It has been generally accepted that the mammalian embryo starts its development with all cells identical, and only when inside and outside cells form do differences between cells first emerge. However, recent findings show that cells in the mouse embryo can differ in their developmental fate and potency as early as the four-cell stage. These differences depend on the orientation and order of the cleavage divisions that generated them. Because epigenetic marks are suggested to be involved in sustaining pluripotency, we considered that such developmental properties might be achieved through epigenetic mechanisms. Here we show that modification of histone H3, through the methylation of specific arginine residues, is correlated with cell fate and potency. Levels of H3 methylation at specific arginine residues are maximal in four-cell blastomeres that will contribute to the inner cell mass (ICM) and polar trophectoderm and undertake full development when combined together in chimaeras. Arginine methylation of H3 is minimal in cells whose progeny contributes more to the mural trophectoderm and that show compromised development when combined in chimaeras. This suggests that higher levels of H3 arginine methylation predispose blastomeres to contribute to the pluripotent cells of the ICM. We confirm this prediction by overexpressing the H3-specific arginine methyltransferase CARM1 in individual blastomeres and show that this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2. Thus, our results identify specific histone modifications as the earliest known epigenetic marker contributing to development of ICM and show that manipulation of epigenetic information influences cell fate determination. 相似文献
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Cyclical DNA methylation of a transcriptionally active promoter 总被引:3,自引:0,他引:3
Métivier R Gallais R Tiffoche C Le Péron C Jurkowska RZ Carmouche RP Ibberson D Barath P Demay F Reid G Benes V Jeltsch A Gannon F Salbert G 《Nature》2008,452(7183):45-50
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Rb targets histone H3 methylation and HP1 to promoters 总被引:78,自引:0,他引:78
Nielsen SJ Schneider R Bauer UM Bannister AJ Morrison A O'Carroll D Firestein R Cleary M Jenuwein T Herrera RE Kouzarides T 《Nature》2001,412(6846):561-565