Abstract
BackgroundHistone 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.ResultsTo 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.ConclusionHDAC activity is required for the expression of critical pro-rod transcription factors and the development of rod photoreceptor cells.
Highlights
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
We have proposed that progenitor cells go through a progression of competency states, each defined by the ability to make different retinal cell types [25]
HDAC activity is required for the expression of critical genes for rod photoreceptor development To determine if HDACs might play a role in retinal development, RT-PCR was used to examine the expression of members of Class I (HDAC1 and 3) and Class II HDACs (HDAC4, 5, and 6) in the developing mouse retina
Summary
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. It is generally believed that HDACs lead to transcription repression as histone hypoacetylation results in a tightly packaged chromatin structure, denying accessibility to transcription regulatory proteins. Histones are not the sole target of HDACs. Other non-histone HDAC substrates include transcription factors, such as E2F1, MyoD, GATA-1, and p53 [5,6,7,8,9], as well as proteins in the cytoplasm, such as tubulin and hsp90 [10,11,12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
