Chen Bo, Cepko Constance L
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
BMC Dev Biol. 2007 Jun 29;7:78. doi: 10.1186/1471-213X-7-78.
Histone deacetylases (HDACs) play a major role in the regulation of gene transcription, often leading to transcriptional repression, as well as other effects following deacetylation of non-histone proteins.
To investigate the role of HDACs in the developing mammalian retina, a general inhibitor of HDACs, trichostatin-A (TSA), was used to treat newborn murine retinae in explant cultures. Inhibition of HDAC activity resulted in a reduction in RNA levels for genes that regulate retinal development, as well as cell cycle regulators. Several of the genes encode transcription factors essential for rod photoreceptor development, Otx2, Nrl, and Crx. Using luciferase reporter assays, the promoter activity of both Nrl and Crx was found to be compromised by HDAC inhibition. Furthermore, downregulation of gene expression by HDAC inhibition didn't require de novo protein synthesis, and was associated with hyperacetylation of histones and non-histone proteins. Finally, HDAC inhibition in retinal explant cultures resulted in increased cell death, reduction in proliferation, a complete loss of rod photoreceptors and Müller glial cells, and an increase in bipolar cells.
HDAC activity is required for the expression of critical pro-rod transcription factors and the development of rod photoreceptor cells.
组蛋白脱乙酰酶（HDACs）在基因转录调控中起主要作用，常导致转录抑制，以及非组蛋白蛋白质脱乙酰化后的其他效应。
为研究HDACs在发育中的哺乳动物视网膜中的作用，使用一种HDACs的通用抑制剂曲古抑菌素A（TSA）处理外植体培养中的新生小鼠视网膜。HDAC活性的抑制导致调节视网膜发育的基因以及细胞周期调节因子的RNA水平降低。其中几个基因编码视杆光感受器发育所必需的转录因子，如Otx2、Nrl和Crx。使用荧光素酶报告基因检测发现，HDAC抑制会损害Nrl和Crx的启动子活性。此外，HDAC抑制引起的基因表达下调不需要从头合成蛋白质，并且与组蛋白和非组蛋白蛋白质的高乙酰化有关。最后，视网膜外植体培养中的HDAC抑制导致细胞死亡增加、增殖减少、视杆光感受器和穆勒神经胶质细胞完全丧失以及双极细胞增加。
HDAC活性是关键的视杆前体转录因子表达和视杆光感受器细胞发育所必需的。
