Requirement of histone deacetylase activity for the expression of critical photoreceptor genes.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
HDAC activity is required for the expression of critical pro-rod transcription factors and the development of rod photoreceptor cells.
Chen
Bo
B
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. bochen@receptor.med.harvard.edu <bochen@receptor.med.harvard.edu>
Cepko
Constance L
CL
D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015536:Down-Regulation; D018274:Electroporation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005136:Eye Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D051857:Otx Transcription Factors / Q000235:genetics; D011401:Promoter Regions, Genetic; D012160:Retina / Q000201:enzymology / Q000254:growth & development*; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology / Q000254:growth & development*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics
C430597:Chrdl1 protein, mouse; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D015534:Trans-Activators; C109288:cone rod homeobox protein; C012589:trichostatin A; D006655:Histone Deacetylases