Ferreira Renata C, Popova Evgenya Y, James Jessica, Briones Marcelo R S, Zhang Samuel S, Barnstable Colin J
From the Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033.
Laboratory of Evolutionary Genomics and Biocomplexity, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil.
J Biol Chem. 2017 Feb 10;292(6):2422-2440. doi: 10.1074/jbc.M116.756643. Epub 2016 Dec 27.
Histone acetylation has a regulatory role in gene expression and is necessary for proper tissue development. To investigate the specific roles of histone deacetylases (HDACs) in rod differentiation in neonatal mouse retinas, we used a pharmacological approach that showed that inhibition of class I but not class IIa HDACs caused the same phenotypic changes seen with broad spectrum HDAC inhibitors, most notably a block in the differentiation of rod photoreceptors. Inhibition of HDAC1 resulted in increase of acetylation of lysine 9 of histone 3 (H3K9) and lysine 12 of histone 4 (H4K12) but not lysine 27 of histone 3 (H3K27) and led to maintained expression of progenitor-specific genes such as and with concomitant block of expression of rod-specific genes. ChiP experiments confirmed these changes in the promoters of a group of progenitor genes. Based on our results, we suggest that HDAC1-specific inhibition prevents progenitor cells of the retina from exiting the cell cycle and differentiating. HDAC1 may be an essential epigenetic regulator of the transition from progenitor cells to terminally differentiated photoreceptors.
组蛋白乙酰化在基因表达中具有调节作用，并且是正常组织发育所必需的。为了研究组蛋白脱乙酰酶（HDACs）在新生小鼠视网膜视杆细胞分化中的具体作用，我们采用了一种药理学方法，结果表明，抑制I类而非IIa类HDACs会导致与广谱HDAC抑制剂相同的表型变化，最显著的是视杆光感受器分化受阻。抑制HDAC1会导致组蛋白3赖氨酸9（H3K9）和组蛋白4赖氨酸12（H4K12）的乙酰化增加，但不会导致组蛋白3赖氨酸27（H3K27）的乙酰化增加，并导致祖细胞特异性基因（如 和 ）的持续表达，同时视杆细胞特异性基因的表达受阻。染色质免疫沉淀（ChiP）实验证实了一组祖细胞基因启动子中的这些变化。基于我们的研究结果，我们认为HDAC1特异性抑制可阻止视网膜祖细胞退出细胞周期并发生分化。HDAC1可能是祖细胞向终末分化光感受器转变过程中必不可少的表观遗传调节因子。
