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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex
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Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

机译：Af9 / Mllt3通过在大脑皮质发育过程中对组蛋白H3K79进行表观遗传修饰来干扰Tbr1表达

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摘要

Mutations of leukemia-associated AF9/MLLT3 are implicated in neu-rodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in post-mitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1 -positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.
机译：白血病相关的AF9 / MLLT3突变与癫痫和共济失调等神经发育疾病有关，但对AF9如何影响大脑发育和功能知之甚少。小鼠突变体的分析显示，在皮质发育过程中，AF9参与了脑室下区域TBR2阳性祖细胞（中间前体细胞，IPC）的维持，并阻止了IPC的细胞周期过早退出。此外，在发育中的皮质板的有丝分裂后神经元中，AF9主要通过抑制上层神经元中的TBR1阳性细胞命运来参与六层大脑皮层的形成。我们表明，TBR1抑制的分子机制是基于AF9与DOT1L的相互作用，DOT1L是一种通过组蛋白H3赖氨酸79（H3K79）的甲基化介导转录控制的蛋白质。 AF9与Tbr1的转录起始位点相关联，介导Tbr1基因的H3K79二甲基化，并干扰Tbr1转录起始位点上RNA聚合酶II的存在。 AF9表达有利于TBR1的胞质定位及其与线粒体的联系。 Af9突变体中TBR1的表达增加与NMDAR亚基Nr1的TBR1调节表达水平升高有关。因此，这项研究确定了AF9是皮层投射神经元生成过程中的发育活性表观遗传修饰因子。

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    Nicole Biittner; Steven A. Johnsen; Sebastian Kuegler; Tanja Vogel;

  • 作者单位

    Centre of Anatomy, Department of Neuroanatomy, University Medical Centre Goettingen, Georg-August-University, 37075 Goettingen, Germany;

    Department of Molecular Oncology, Goettingen Center for Molecular Biosciences, Georg-August-University, 37077 Goettingen, Germany;

    DFG Research Center Molecular Physiology of the Brain at Department of Neurology, University Medical Centre Goettingen, Georg-August-University, 37073 Goettingen, Germany;

    Centre of Anatomy, Department of Neuroanatomy, University Medical Centre Goettingen, Georg-August-University, 37075 Goettingen, Germany;

  • 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
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  • 关键词

    Tbr2; histone methylation; upper layer neurons; dot1l; Nr1;

    机译：Tbr2;组蛋白甲基化上层神经元dot1l;1号;

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