TGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.

TitleTGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.
Publication TypeJournal Article
Year of Publication2013
AuthorsKato M, Dang V, Wang M, Park JT, Deshpande S, Kadam S, Mardiros A, Zhan Y, Oettgen P, Putta S, Yuan H, Lanting L, Natarajan R
JournalScience signaling
Volume6
Issue278
Paginationra43
Date Published2013 Jun 4
Abstract

MicroRNAs (miRNAs), such as miR-192, mediate the actions of transforming growth factor-β1 (TGF-β) related to the pathogenesis of diabetic kidney diseases. We found that the biphasic induction of miR-192 expression by TGF-β in mouse renal glomerular mesangial cells initially involved the Smad transcription factors, followed by sustained expression that was promoted by acetylation of the transcription factor Ets-1 and of histone H3 by the acetyltransferase p300, which was activated by the serine and threonine kinase Akt. In mesangial cells from Ets-1-deficient mice or in cells in which Ets-1 was knocked down, basal amounts of miR-192 were higher than those in control cells, but sustained induction of miR-192 by TGF-β was attenuated. Furthermore, inhibition of Akt or ectopic expression of dominant-negative histone acetyltransferases decreased p300-mediated acetylation and Ets-1 dissociation from the miR-192 promoter and prevented miR-192 expression in response to TGF-β. Activation of Akt and p300 and acetylation of Ets-1 and histone H3 were increased in glomeruli from diabetic db/db mice compared to nondiabetic db/+ mice, suggesting that this pathway may contribute to diabetic nephropathy. These findings provide insight into the regulation of miRNAs through signaling-mediated changes in transcription factor activity and in epigenetic histone acetylation under normal and disease states.

DOI10.1371/journal.pone.0077446
Alternate JournalSci Signal