Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3. In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.

中文翻译：

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HDAC3 通过 NCoR/SMRT 依赖机制确保逐步表皮分层，而与其组蛋白脱乙酰酶活性无关。

染色质修饰剂在表皮发育中起着关键作用，但人们对组蛋白脱乙酰酶在这方面的功能知之甚少。I 类 HDAC HDAC3 特别令人感兴趣，因为它通过与组织特异性转录因子合作在不同组织中发挥不同的作用。我们发现 HDAC3 在胚胎表皮中广泛表达，并且是其有序逐步分层所必需的。HDAC3 蛋白在体内的稳定性依赖于 NCoR 和 SMRT，它们在表皮发育中发挥着冗余作用。然而，HDAC3 酶功能所需的 NCoR 和 SMRT 脱乙酰酶激活域中的点突变允许正常分层，表明 HDAC3 在这种情况下的作用在很大程度上独立于其组蛋白脱乙酰酶活性。HDAC3 结合位点显着丰富了关键表皮转录因子（包括 AP1、GRHL 和 KLF 家族成员）的预测结合基序。我们的结果表明，在这些之中，HDAC3 与 KLF4 一起运作以抑制不适当的表达Tgm1、Krt16和Aqp3。同时，HDAC3 通过Rela依赖性机制抑制炎性细胞因子的表达。这些数据将 HDAC3 确定为协调表皮屏障获取的多个方面的枢纽。