小柯机器人

Brahma保障心脏中胚层分化的限向
2022-01-30 23:39
来源：小柯机器人

美国加州大学旧金山分校Benoit G. Bruneau、Swetansu K. Hota等研究人员合作发现，Brahma保障心脏中胚层分化的限向。这一研究成果于2022年1月26日在线发表在国际学术期刊《自然》上。

研究人员发现，BRG1/BRM相关因子（BAF）染色质重塑复合物ATP酶基因Brm在小鼠胚胎干细胞的定向心脏发育过程中保障了细胞的身份。尽管建立了分化良好的心前中胚层，但Brm-/-细胞主要成为神经前体，违反了生殖层分配。轨迹推断显示Brm-/-细胞突然获得了非中胚层身份。从机制上讲，Brm的缺失阻止了原始心脏增强子的从头可及性，同时增加了神经源性因子POU3F1的表达，阻止了神经抑制因子REST的结合并改变了BRG1复合物的组成。在中胚层诱导过程中，通过提高BMP4水平克服了Brm突变引起的身份转换。
 
数学模型支持这些观察，并证明Brm缺失通过修改鞍结分叉（saddle–node bifurcations）影响细胞命运轨迹。在小鼠胚胎中，Brm缺失加剧了中胚层缺失Brg1突变体的表型，严重损害了心脏发育，并揭示了Brm在体内的作用。这些研究结果表明，Brm是中胚层染色质状态保真度的一个可补偿保障，并支持一个模型：发育限向不是一个刚性的不可逆转的路径，而是一个高度可塑性的轨迹。
 
据介绍，分化是沿着越来越受命运限制的中间阶段连续进行的，被称为限向（canalization）。限向是稳定细胞命运的必要条件，但支撑强大限向的机制尚不清楚。
 
附：英文原文
 
Title: Brahma safeguards canalization of cardiac mesoderm differentiation

Author: Hota, Swetansu K., Rao, Kavitha S., Blair, Andrew P., Khalilimeybodi, Ali, Hu, Kevin M., Thomas, Reuben, So, Kevin, Kameswaran, Vasumathi, Xu, Jiewei, Polacco, Benjamin J., Desai, Ravi V., Chatterjee, Nilanjana, Hsu, Austin, Muncie, Jonathon M., Blotnick, Aaron M., Winchester, Sarah A. B., Weinberger, Leor S., Httenhain, Ruth, Kathiriya, Irfan S., Krogan, Nevan J., Saucerman, Jeffrey J., Bruneau, Benoit G.

Issue&Volume: 2022-01-26

Abstract: Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm/ cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm/ cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle–node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

DOI: 10.1038/s41586-021-04336-y

Source: https://www.nature.com/articles/s41586-021-04336-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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