Chromatin remodeler Dmp18 regulates apoptosis by controlling H2Av incorporation in Drosophila imaginal disc development.
Chromatin remodeler Dmp18 regulates apoptosis by controlling H2Av incorporation in Drosophila imaginal disc development.
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染色质重塑剂 Dmp18 通过控制果蝇成虫盘发育中的 H2Av 掺入来调节细胞凋亡
DOI：
10.1371/journal.pgen.1010395
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发表时间：
2022-09
期刊：
影响因子：
4.5
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中科院分区：
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程序性细胞死亡（PCD）或细胞凋亡是一种高度保守的生物过程，在发育和应激环境中发挥着重要作用。在果蝇中，促凋亡基因的表达，包括收割者（rpr）、头部复旧缺陷（hid）、严峻和镰状（skl），足以诱导细胞死亡。在这里，我们证明染色质重塑剂 Dmp18（哺乳动物 Zhit1 的同源物）在调节眼睛和翅膀发育中的细胞凋亡中发挥着至关重要的作用。我们发现 Dmp18 的缺失会扰乱眼睛和翅膀的发育，上调促凋亡基因的转录，并诱导细胞凋亡。抑制细胞凋亡可抑制 Dmp18 缺失引起的眼部缺陷。此外，Dmp18 的缺失破坏了 H2Av 掺入染色质，促进了 H3K4me3，但减少了促凋亡基因 TSS 区域的 H3K27me3 修饰。这些结果表明，Dmp18 通过介导 H2Av 掺入和促凋亡基因位点的组蛋白 H3 修饰进行转录调控，从而负向调节细胞凋亡。我们的研究揭示了 Dmp18 在调节果蝇眼睛和翅膀发育中细胞凋亡中的作用，并提供了在表观遗传水平上调节细胞凋亡的染色质重塑的见解。细胞凋亡是发育和应激环境中的一个重要生物过程，通过去除不需要的或受损的细胞。细胞凋亡失调会导致包括癌症在内的许多疾病。促凋亡基因的转录诱导足以诱导果蝇细胞凋亡。 Zhnit1 编码含有锌指 HIT 型的蛋白质，并作为酵母和哺乳动物染色质重塑复合物的组成部分。在当前的研究中，我们发现 Zhit1 的同源物 Dmp18 通过介导促凋亡基因转录起始位点 (TSS) 区域周围的组蛋白变体 H2Av 掺入和 H3K4me3 以及 H3K27me3 修饰来调节细胞凋亡。 Dmp18 缺失上调了促凋亡基因（包括 rpr 和 hid）的转录，引发大量细胞死亡，并导致眼睛和翅膀缺陷。重要的是，Dmp18 的缺失破坏了 H2Av 与染色质的整合，增加了 H3K4me3，但减少了促凋亡基因 TSS 区域上用于转录激活的 H3K27me3 修饰。总之，这项研究揭示了 Dmp18 调节眼盘和翼盘细胞凋亡的机制。
Programmed Cell Death (PCD) or apoptosis is a highly conserved biological process and plays essential roles both in the development and stress context. In Drosophila, expression of pro-apoptotic genes, including reaper (rpr), head involution defective (hid), grim, and sickle (skl), is sufficient to induce cell death. Here, we demonstrate that the chromatin remodeler Dmp18, the homolog of mammalian Znhit1, plays a crucial role in regulating apoptosis in eye and wing development. We showed that loss of Dmp18 disrupted eye and wing development, up-regulated transcription of pro-apoptotic genes, and induced apoptosis. Inhibition of apoptosis suppressed the eye defects caused by Dmp18 deletion. Furthermore, loss of Dmp18 disrupted H2Av incorporation into chromatin, promoted H3K4me3, but reduced H3K27me3 modifications on the TSS regions of pro-apoptotic genes. These results indicate that Dmp18 negatively regulates apoptosis by mediating H2Av incorporation and histone H3 modifications at pro-apoptotic gene loci for transcriptional regulation. Our study uncovers the role of Dmp18 in regulating apoptosis in Drosophila eye and wing development and provides insights into chromatin remodeling regulating apoptosis at the epigenetic levels. Apoptosis is an important biological process in the development and stress context by removing unwanted or damaged cells. Dysregulation of apoptosis causes many diseases including cancers. Transcriptional induction of pro-apoptotic genes is sufficient to induce apoptosis in Drosophila. Znhit1 encodes a Zinc finger HIT-type containing protein and works as a component of the chromatin remodeling complex in yeast and mammals. In the current study, we identified that Dmp18, the homolog of Znhit1, regulates apoptosis by mediating the histone variant H2Av incorporation and H3K4me3 as well as H3K27me3 modifications around the transcription start site (TSS) regions of pro-apoptotic genes. Dmp18 deletion up-regulated the transcription of pro-apoptotic genes including rpr and hid, triggered massive cell death, and resulted in eye and wing defects. Importantly, loss of Dmp18 disrupted H2Av incorporation into chromatin, increased H3K4me3, but decreased H3K27me3 modifications on the TSS regions of pro-apoptotic genes for transcriptional activation. Together, this study reveals the mechanism by which Dmp18 regulates apoptosis in the eye and wing discs.
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