GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism.
GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism.
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DOI：
10.1016/j.devcel.2018.07.022
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发表时间：
2018-09-10
影响因子：
11.8
通讯作者：
Bresnick EH
中科院分区：
文献类型：
--
作者：
Tanimura N;Liao R;Wilson GM;Dent MR;Cao M;Burstyn JN;Hematti P;Liu X;Zhang Y;Zheng Y;Keles S;Xu J;Coon JJ;Bresnick EH
血红素作为一种酶辅因子、血红蛋白组分和基因调节剂，对生命至关重要。血红素调节的转录的一种模式涉及放大加塔-1的活性，其是红细胞分化的关键决定因素。为了发现金属辅因子-转录因子机制的生物学后果，我们合并了蛋白质组和转录组的加塔-1/血红素调节部分。这种多组学分析揭示了一个加塔-1/血红素电路，涉及血红蛋白亚基，泛素化成分，和蛋白质不涉及红细胞生物学，包括锌输出Slc 30 a1。虽然加塔-1诱导表达的Slc 30 a1和锌的进口商Slc 39 a8，Slc 39 a8主要增加细胞内锌，这赋予成红细胞的生存。随后，锌转运开关，涉及进口商和持续出口商的表达减少，减少细胞内锌在终端分化。下调Slc 30 a1增加细胞内锌，并显著加速分化。该分析建立了一个保守的范例，其中加塔-1/血红素电路控制微量金属转运机制和微量金属水平作为一种机制，管理细胞分化。锌缺乏症通过知之甚少的机制引起贫血。Tanimura等人报告称，红细胞发育的主要决定因素加塔-1和血红蛋白合成的重要辅因子血红素控制着锌水平。锌水平反过来调节红细胞发育，从而建立一个范式，通知贫血机制。
By functioning as an enzyme cofactor, hemoglobin component and gene regulator, heme is vital for life. One mode of heme-regulated transcription involves amplifying the activity of GATA-1, a key determinant of erythrocyte differentiation. To discover biological consequences of the metal cofactor-transcription factor mechanism, we merged GATA-1/heme-regulated sectors of the proteome and transcriptome. This multi-omic analysis revealed a GATA-1/heme circuit involving hemoglobin subunits, ubiquitination components, and proteins not implicated in erythrocyte biology, including the zinc exporter Slc30a1. Though GATA-1 induced expression of Slc30a1 and the zinc importer Slc39a8, Slc39a8 dominantly increased intracellular zinc, which conferred erythroblast survival. Subsequently, a zinc transporter switch, involving decreased importer and sustained exporter expression, reduced intracellular zinc during terminal differentiation. Downregulating Slc30a1 increased intracellular zinc and, strikingly, accelerated differentiation. This analysis established a conserved paradigm in which a GATA-1/heme circuit controls trace metal transport machinery and trace metal levels as a mechanism governing cellular differentiation. Zinc deficiency causes anemia through poorly understood mechanisms. Tanimura et al. report that GATA-1, a major determinant of red blood cell development, and heme, an essential cofactor for hemoglobin synthesis, control zinc levels. Zinc levels in turn regulate red blood cell development, thereby establishing a paradigm that informs anemia mechanisms.
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影响因子：
5.3
作者：
Kang, Yoon-A;Sanalkumar, Rajendran;Bresnick, Emery H.
通讯作者：
Bresnick, Emery H.
影响因子：
16
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1.5
作者：
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