Repression of Six3 by a corepressor regulates rhodopsin expression.
Here, we provide gain-of-function, loss-of function, and molecular evidence supporting genetic interactions between metastasis associated protein 1 (MTA1) and Six3 and between Six3 and rhodopsin. We discovered that MTA1 physically interacts with the Six3 chromatin in a histone deacetylase-dependent manner, leading to transcriptional suppression of the Six3 gene. MTA1 is also a Six3-interacting corepressor that contributes to a self-negative regulation of Six3 transcription by Six3. In contrast, deletion of the MTA1 alleles in murine embryonic fibroblasts or its knockdown in rat retinal ganglion cells stimulates Six3 expression. MTA1 inactivation in the MTA1-null mice results in an elevated Six3 level and proliferation of the retina cells with no obvious abnormities in eye formation. However, unexpectedly, we discovered an enhanced recruitment of Six3 to the rhodopsin chromatin in retina from the MTA1-null mice; Six3's homeodomain interacts with specific DNA elements in the rhodopsin promoter to stimulate its transcription, resulting in increased rhodopsin expression. Further, in holoprosencephaly patients, Six3 protein with a naturally occurring deletion mutation in the helix 3 of the homeodomain does not bind to rhodopsin DNA or stimulate rhodopsin transcription, implying a potential defective rhodopsin pathway in the affected holoprosencephaly patients. Further Six3 cooperates with Crx or NRL in stimulating transcription from the rhodopsin-luc. These findings reveal a previously unrecognized role for the MTA1 as an upstream modifier of Six3 and indicate that Six3 is a direct stimulator of rhodopsin expression, thus revealing a putative role for the MTA1/Six3/rhodopsin pathway in vertebrate eye.
Manavathi
Bramanandam
B
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Peng
Shaohua
S
Rayala
Suresh K
SK
Talukder
Amjad H
AH
Wang
Minhua H
MH
Wang
Rui-An
RA
Balasenthil
Seetharaman
S
Agarwal
Neeraj
N
Frishman
Laura J
LJ
Kumar
Rakesh
R
D000818:Animals; D005136:Eye Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D012243:Rhodopsin / Q000235:genetics*; D015534:Trans-Activators; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D012243:Rhodopsin; D015534:Trans-Activators; D000097607:Homeobox Protein SIX3; C089320:MTA1 protein, human