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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Building multifunctionality into a complex containing master regulators of hematopoiesis
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Building multifunctionality into a complex containing master regulators of hematopoiesis

机译：将多功能性构建到包含造血功能主要调节剂的复合物中

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摘要

Developmental control mechanisms often use multimeric complexes containing transcription factors, coregulators, and additional non-DNA binding components. It is challenging to ascertain how such components contribute to complex function at endogenous loci. We analyzed the function of components of a complex containing master regulators of hematopoiesis (GATA-1 and Scl/TAL1) and the non-DNA binding components ETO2, the LIM domain protein LMO2, and the chromatin looping factor LDB1. Surprisingly, we discovered that ETO2 and LMO2 regulate distinct target-gene ensembles in erythroid cells. ETO2 commonly repressed GATA-1 function via suppressing histone H3 acetylation, although it also regulated methyl-ation of histone H3 at lysine 27 at select loci. Prior studies defined multiple modes by which GATA-1 regulates target genes with or without the coregulator Friend of GATA-1 (FOG-1). LMO2 selectively repressed genes that GATA-1 represses in a FOG-1-independent manner. As LMO2 controls hematopoiesis, its dysregulation is leu-kemogenic, and its influence on GATA factor function is unknown, this mechanistic link has important biological and pathophysio-logical implications. The demonstration that ETO2 and LMO2 exert qualitatively distinct functions at endogenous loci illustrates how components of complexes containing master developmental regulators can impart the capacity to regulate unique cohorts of target genes, thereby diversifying complex function.
机译：发展控制机制通常使用包含转录因子，共调节因子和其他非DNA结合成分的多聚体复合物。确定这些成分如何促进内源基因座的复杂功能具有挑战性。我们分析了包含造血功能的主调节因子（GATA-1和Scl / TAL1）和非DNA结合成分ETO2，LIM域蛋白LMO2和染色质环化因子LDB1的复合物的功能。出乎意料的是，我们发现ETO2和LMO2调节类红细胞中不同的靶基因集合。 ETO2通常通过抑制组蛋白H3的乙酰化来抑制GATA-1的功能，尽管ETO2还可以调节选定位点赖氨酸27处组蛋白H3的甲基化。先前的研究定义了GATA-1在有或没有GATA-1核心调节剂之友（FOG-1）的情况下调节靶基因的多种模式。 LMO2选择性抑制以FOG-1独立的方式抑制GATA-1的基因。由于LMO2控制着造血作用，其失调是致白细胞生成，并且其对GATA因子功能的影响尚不清楚，这种机理联系具有重要的生物学和病理生理学意义。 ETO2和LMO2在内源基因座上定性地发挥不同功能的论证说明了含有主要发育调节因子的复合物成分如何赋予调节靶基因独特队列的能力，从而使复合物功能多样化。

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    Tohru Fujiwara; Hsiang-Ying Lee; Rajendran Sanalkumar; Emery H. Bresnick;

  • 作者单位

    Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health,Madison, WI 53705;

    Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health,Madison, WI 53705;

    Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health,Madison, WI 53705;

    Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health,Madison, WI 53705;

  • 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

    blood; hematopoietic; genetic network; leukemia; progenitor cell;

    机译：血液;造血的遗传网络;白血病;祖细胞;

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