Abstract：
Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.
摘要：
雪旺氏细胞功能障碍，包括细胞凋亡，自噬抑制，去分化，和焦亡，是诱发糖尿病周围神经病变（DPN）的关键致病因素。组蛋白脱乙酰酶（HDAC）是一个重要的蛋白质家族，通过影响染色质动力学来表观遗传调节基因转录。这里,我们探讨了HDAC1对高糖培养的雪旺细胞的影响。HDAC1在糖尿病小鼠和高糖培养的RSC96细胞中表达增加，伴随细胞凋亡。高糖还增加了线粒体途径凋亡相关的Bax/Bcl-2和caspase-9/caspase-9的比例，并降低了内质网反应相关的GRP78，CHOP，和ATF4在RSC96细胞中的表达(P<0.05)。此外，HDAC1的过表达增加Bax/Bcl-2，caspase-9/caspase-9和caspase-3的比例，并降低GRP78，CHOP，和ATF4在RSC96细胞中的表达(P<0.05)。相比之下,HDAC1敲除抑制高糖促进的线粒体途径凋亡并抑制内质网反应。此外，RNA测序显示U4剪接体RNA在HDAC1过表达的RSC96细胞中显著减少。U4剪接体RNA的沉默导致Bax/Bcl-2和裂解的半胱天冬酶-9的增加以及CHOP和ATF4的减少。相反，U4剪接体RNA的过表达阻断HDAC1促进线粒体途径凋亡并抑制内质网反应。此外,HDAC1过表达RSC96细胞的选择性剪接分析表明，Rpl21，Cdc34和Mtmr11的显着差异内含子保留（IR）可能是介导U4缺陷诱导的雪旺氏细胞功能障碍的主要下游靶标。一起来看,这些结果表明,HDAC1通过降低Rpl21,Cdc34和Mtmr11的U4剪接体RNA/IR,促进线粒体途径介导的细胞凋亡,抑制高糖培养的雪旺细胞内质网应激反应.
