HDAC1 and HDAC2 independently regulate common and specific intrinsic responses in murine enteroids
HDAC1 and HDAC2 independently regulate common and specific intrinsic responses in murine enteroids
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DOI：
10.1038/s41598-019-41842-6
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发表时间：
2019-03-29
影响因子：
4.6
通讯作者：
Asselin, Claude
中科院分区：
文献类型：
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作者：
Gonneaud, Alexis;Turgeon, Naomie;Asselin, Claude
HDAC 1和HDAC 2都是I类脱乙酰酶，作为组蛋白和非组蛋白上赖氨酸-乙酰标记的擦除剂。几种组蛋白脱乙酰酶抑制剂，无论是内源性的细胞，如生酮β-羟基丁酸代谢物，或外源性的，如丁酸，微生物衍生的代谢物，调节HDAC活性。肠上皮细胞（IEC）特异性Hdac 1和/或Hdac 2缺失的不同组合差异性地改变小鼠的粘膜稳态。因此，HDAC 1和HDAC 2可以作为环境信号的传感器和传递器到粘膜。在这项研究中，建立了删除Hdac 1或Hdac 2的肠样培养模型，以确定IEC特异性功能，并通过全球转录组学和蛋白质组学方法进行评估。结果表明，Hdac 1或Hdac 2缺陷改变了维持物理和化学保护屏障的潘氏和杯状分泌细胞的分化，并增加了中间分泌细胞前体的数量。此外，IEC Hdac 1-和Hdac 2-依赖的共同和特定的生物过程被确定，包括氧化还原，炎症反应，和脂质相关的代谢过程，以及典型的途径和上游调控相关的环境依赖性信号通过类固醇受体途径，等等。这些发现揭示了IEC中Hdac 1和Hdac 2之间未被识别的调节相似性和差异，并证明了HDAC 1和HDAC 2如何相互补充以调节固有的IEC表型。
Both HDAC1 and HDAC2 are class I deacetylases acting as erasers of lysine-acetyl marks on histones and non-histone proteins. Several histone deacetylase inhibitors, either endogenous to the cell, such as the ketogenic beta-hydroxybutyrate metabolite, or exogenous, such as butyrate, a microbial-derived metabolite, regulate HDAC activity. Different combinations of intestinal epithelial cell (IEC)-specific Hdac1 and/or Hdac2 deletion differentially alter mucosal homeostasis in mice. Thus, HDAC1 and HDAC2 could act as sensors and transmitters of environmental signals to the mucosa. In this study, enteroid culture models deleted for Hdac1 or Hdac2 were established to determine IEC-specific function as assessed by global transcriptomic and proteomic approaches. Results show that Hdac1 or Hdac2 deficiency altered differentiation of Paneth and goblet secretory cells, which sustain physical and chemical protection barriers, and increased intermediate secretory cell precursor numbers. Furthermore, IEC Hdac1-and Hdac2-dependent common and specific biological processes were identified, including oxidation-reduction, inflammatory responses, and lipid-related metabolic processes, as well as canonical pathways and upstream regulators related to environment-dependent signaling through steroid receptor pathways, among others. These findings uncover unrecognized regulatory similarities and differences between Hdac1 and Hdac2 in IEC, and demonstrate how HDAC1 and HDAC2 may complement each other to regulate the intrinsic IEC phenotype.