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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human BAHD1 promotes heterochromatic gene silencing
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Human BAHD1 promotes heterochromatic gene silencing

机译：人类BAHD1促进异色基因沉默

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摘要

Gene silencing via heterochromatin formation plays a major role in cell differentiation and maintenance of homeostasis. Here we report the identification and characterization of a novel heterochromatini-zation factor in vertebrates, bromo adjacent homology domain-containing protein 1 (BAHD1). This nuclear protein interacts with HP1, MBD1, HDAC5, and several transcription factors. Through electron and immunofluorescence microscopy studies, we show that BAHD1 overexpression directs HP1 to specific nuclear sites and promotes the formation of large heterochromatic domains, which lack acetyl his-tone H4 and are enriched in H3 trimethylated at lysine 27 (H3K27me3). Furthermore, ectopically expressed BAHD1 colocalizes with the heterochromatic inactive X chromosome (Xi). The BAH domain is required for BAHD1 colocalization with H3K27me3, but not with the Xi chromosome. As highlighted by whole genome microarray analysis of BAHD1 knockdown cells, BAHD1 represses several proliferation and survival genes, in particular the insulin-like growth factor II gene (IGF2). When overexpressed, BAHD1 specifically binds the CpG-rich P3 promoter of IGF2, which increases MBD1 and HDAC5 targeting at this locus. This region contains DNA-binding sequences for the transcription factor SP1, with which BAHD1 coimmunoprecipitates. Collectively, these findings provide evidence that BAHD1 acts as a silencer by recruiting at specific promoters a set of proteins that coordinate heterochromatin assembly.
机译：通过异染色质形成的基因沉默在细胞分化和维持体内平衡中起着重要作用。在这里，我们报告在脊椎动物，溴相邻同源域包含蛋白1（BAHD1）中的新型异染色质化因子的鉴定和表征。该核蛋白与HP1，MBD1，HDAC5和几种转录因子相互作用。通过电子和免疫荧光显微镜研究，我们显示BAHD1过表达将HP1引导到特定的核位点并促进形成大型异色域，这些域缺少乙酰基组蛋白H4并富含赖氨酸27（H3K27me3）上的三甲基化H3。此外，异位表达的BAHD1与非活性X染色体（Xi）共定位。 BAHD1与H3K27me3（而非Xi染色体）共定位时，需要BAH域。正如对BAHD1敲除细胞的全基因组微阵列分析所强调的那样，BAHD1抑制了几个增殖和存活基因，特别是胰岛素样生长因子II基因（IGF2）。当过表达时，BAHD1特异性结合IGF2的富含CpG的P3启动子，从而增加针对该基因位的MBD1和HDAC5。该区域包含转录因子SP1的DNA结合序列，BAHD1与之进行免疫共沉淀。总而言之，这些发现提供了证据，证明BAHD1通过在特定启动子募集协调异染色质装配的蛋白质来充当沉默子。

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  • 作者

    Helene Bierne; To Nam Tham; Eric Batsche; Anne Dumay; Morwenna Leguillou; Sophie Kerneis-Golsteyn; Beatrice Regnault; Jacob S. Seeler; Christian Muchardt; Jean Feunteun; Pascale Cossart;

  • 作者单位

    Institut Pasteur, Unite des Interactions Bacteries Cellules, Inserm U604, and INRA USC2020, Paris, F-75015, France;

    Institut Pasteur, Unite des Interactions Bacteries Cellules, Inserm U604, and INRA USC2020, Paris, F-75015, France;

    Institut Pasteur, Unite de Regulation Epigenetique, INSERM Avenir, CNRS URA 2578, Paris, F-75015, France;

    Laboratoire Genomes et Cancers, FRE CNRS 2939, Villejuif, F-94805, France;

    Laboratoire Genomes et Cancers, FRE CNRS 2939, Villejuif, F-94805, France;

    Institut Pasteur, Plate-forme de Microscopie Electronique, Paris, F-75015, France;

    Institut Pasteur, Plate-forme Puces a ADN, Paris, F-75015, France;

    Institut Pasteur, Unite Organisation Nucleaire et Oncogenese, INSERM U579, Paris, F-75015, France;

    Institut Pasteur, Unite de Regulation Epigenetique, INSERM Avenir, CNRS URA 2578, Paris, F-75015, France;

    Laboratoire Genomes et Cancers, FRE CNRS 2939, Villejuif, F-94805, France;

    Institut Pasteur, Unite des Interactions Bacteries Cellules, Inserm U604, and INRA USC2020, Paris, F-75015, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    BAH domain; epigenetics; heterochromatin; HP1; polycomb;

    机译：BAH域;表观遗传学异染色质HP1;聚梳;

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