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Topoisomerases facilitate transcription of long genes linked to autism

机译:拓扑异构酶促进与自闭症有关的长基因的转录

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Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOPI) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Topi or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOPI inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.%拓扑异构酶(DNA卷绕中所涉及的酶)在整个大 脑中都有表达,同时相关突变已在一些"泛自 闭症"(ASD)患者中被发现。Mark Zylka及同 事发现,选择性降低拓扑异构酶活性,会通过 影响"转录伸长"降低"长基因"在小鼠和人类 神经元中的表达。作者指出,很多ASD候选基 因(包括Cntnap2、 Nrxn7和Cntn4)特别长,并 且证实几种ASD候选基因的表达被拓扑异构酶 的抑制降低。这些发现表明,影响拓扑异构酶 的化学物质和基因突变(也包括转录机构的其 他部分)可能有助于ASD和其他神经发育疾病 的发生。
机译:拓扑异构酶在整个发育中的大脑和成年大脑中表达,并在某些患有自闭症谱系障碍(ASD)的个体中发生突变。然而,拓扑异构酶如何与ASD机械连接是未知的。在这里,我们发现拓扑异构酶1(TOPI)抑制剂Topotecan剂量依赖性地降低了小鼠和人类神经元中极长基因的表达,包括几乎所有长度超过200千碱基的基因。在敲除神经元中的Topi或Top2b后,长基因的表达也减少了,这突出了这两种酶是长基因完整表达所必需的。通过在神经元全基因组范围内绘制RNA聚合酶II密度,我们发现这种对基因表达的长度依赖性效应是由于转录延伸受损。有趣的是,许多高可信度的ASD候选基因都异常长,并且在抑制TOPI后表达降低。我们的发现表明,损害拓扑异构酶的化学物质和遗传突变通常可导致ASD和其他神经发育障碍。%拓扑变异酶(DNA代谢中所涉及的酶)在整个大脑中都有表达,同时相关相关突变已在Mark Zylka及同事发现,选择性降低突变替代酶活性,会通过影响“转录扩展”降低“长基因”在小鼠和人类神经中元中的表达。作者指出,很多ASD取代基因(包括Cntnap2,Nrxn7和Cntn4)特别长,并且并同时替代了ASD特定基因的表达被取代的酶的抑制降低。这些发现表明,影响拓扑异质构酶的化学物质和基因突变(也包括转录机构的其他部分)可能导致ASD和其他神经发育疾病的发生。

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  • 来源
    《Nature》 |2013年第7465期|58-62A3|共6页
  • 作者单位

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA;

    Carolina Institute for Developmental Disabilities ,The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA;

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA,Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan;

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA;

    Departmentof Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Departmentof Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Departmentof Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA,Lineberger Comprehensive Cancer Center,The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Departmentof Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA,Lineberger Comprehensive Cancer Center,The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA;

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA,Carolina Institute for Developmental Disabilities ,The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA,UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Ceil Biology and Physiology ,The University of North Carolina at Cha pel Hill, Chapel Hill, North Carolina 27599, USA,Carolina Institute for Developmental Disabilities ,The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA,UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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  • 入库时间 2022-08-18 02:53:44

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