A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in β-globin expression and erythroid development
A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in β-globin expression and erythroid development
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DOI：
10.1101/gad.1364105
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发表时间：
2005-12-01
影响因子：
10.5
通讯作者：
Magnuson, T
中科院分区：
文献类型：
--
作者：
Bultman, SJ;Gebuhr, TC;Magnuson, T
SWI/SNF相关复合物的Brg 1催化亚基参与了许多发育和生理过程，但无效纯合子在植入前作为囊胚死亡。为了避免这种早期胚胎致死性，我们进行了ENU诱变筛选，并在ATP酶结构域中产生了Brg 1亚型突变。突变体Brg 1蛋白是稳定的，组装成SWI/SNF相关的复合物，并表现出正常的ATP酶活性，但不能建立开放染色质特征的DNase I超敏位点。突变胚胎正常发育，直到妊娠中期，但随后在红细胞谱系的发育中表现出明显的阻滞，导致贫血和死亡。突变的Brg 1蛋白被募集到β-珠蛋白基因座，但染色质重塑和转录受到干扰。组蛋白乙酰化和DNA甲基化也受到影响。据我们所知，Brg 1是第一个染色质修饰因子显示需要在体内P-珠蛋白调节和红细胞生成。这种突变不仅确定了Brg 1在器官发生过程中的作用，还表明ATP酶活性可以与染色质重塑脱钩。
The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in many developmental and physiological processes, but null homozygotes die as blastocysts prior to implantation. To circumvent this early embryonic lethality, we performed an ENU mutagenesis screen and generated a Brg1 hypomorph mutation in the ATPase domain. The mutant Brg1 protein is stable, assembles into SWI/SNF-related complexes, and exhibits normal ATPase activity but is unable to establish DNase I hypersensitivity sites characteristic of open chromatin. Mutant embryos develop normally until midgestation but then exhibit a distinct block in the development of the erythroid lineage, leading to anemia and death. The mutant Brg1 protein is recruited to the p-globin locus, but chromatin remodeling and transcription are perturbed. Histone acetylation and DNA methylation are also affected. To our knowledge, Brg1 is the first chromatin-modifying factor shown to be required for P-globin regulation and erythropoiesis in vivo. Not only does this mutation establish a role for Brg1 during organogenesis, it also demonstrates that ATPase activity can be uncoupled from chromatin remodeling.