Asymmetric Segregation of the Nucleosome Remodeling and Deacetylase Complex during Asymmetric Cell Divisions

Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates. Epigenetic mechanisms are crucial for cell fate specification, and it remains unclear how epigenetic information is inherited. Here, we report asymmetric segregation of the nucleosome remodeling and deacetylase complex (NuRD) during ACDs in Caenorhabditis elegans. NuR­D is enriched to chromosomes of the future surviving but not apoptotic daughter cell, whereas NuRD evenly distributes to two viable siblings. Disruption of ACDs causes symmetric NuRD inheritance, and an ectopic gain of NuRD in apoptotic daughters allows cell survival and differentiation. Lack of NuRD upregulates the expression of the vital cell death-inducing gene egl-1 by increasing H3K27 acetylation on the egl-1 locus, which activates the EGL-1-CED-9-CED-4-CED-3 pathway to promote apoptosis. We propose that biased NuRD segregation during ACDs provides a previously unrecognized yet common mechanism for asymmetrically partitioning epigenetic information that contributes to binary cell fate decisions. Overall design: 1.The embryonic SPLiT-seq of wild-type worms expressing Pegl-1::NLS::gfp;2.Embryonic mRNA profiles of wild type and hda-1/lin-53 RNAi worms;3. Examination of H3K27ac modifications in wild type and hda-1/lin-53 RNAi worms.

不对称细胞分裂（asymmetric cell divisions, ACDs）可产生遗传信息完全一致，但细胞命运截然不同的两个子细胞。表观遗传机制在细胞命运特化过程中发挥关键作用，然而目前学界尚未明确表观遗传信息的传递机制。本研究报道了秀丽隐杆线虫（Caenorhabditis elegans）在ACDs过程中，核小体重塑与去乙酰化酶复合物（nucleosome remodeling and deacetylase complex, NuRD）的不对称分离现象：NuRD特异性富集于将存活而非发生凋亡的子细胞的染色体中，而在两个存活的子代细胞内则呈均匀分布状态。破坏ACDs会导致NuRD的对称遗传；而在凋亡子细胞中异位获得NuRD，则可使该细胞获得存活能力并完成分化。NuRD缺失会通过提高egl-1基因座上的H3K27乙酰化水平，上调促细胞死亡关键基因egl-1的表达，进而激活EGL-1-CED-9-CED-4-CED-3通路以促进细胞凋亡。我们提出，ACDs过程中NuRD的偏向性分离，为不对称分配表观遗传信息提供了一种此前未被认知但广泛存在的机制，该机制可调控二元细胞命运的决定过程。
整体实验设计：
1. 对表达Pegl-1::NLS::gfp的野生型线虫进行胚胎SPLiT-seq分析；
2. 分析野生型与hda-1/lin-53 RNA干扰（RNA interference, RNAi）线虫的胚胎mRNA表达谱；
3. 检测野生型与hda-1/lin-53 RNAi线虫的H3K27乙酰化修饰水平。