RT Journal Article
SR Electronic
T1 TGF-β Induces Acetylation of Chromatin and of Ets-1 to Alleviate Repression of miR-192 in Diabetic Nephropathy
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra43
OP ra43
DO 10.1126/scisignal.2003389
VO 6
IS 278
A1 Kato, Mitsuo
A1 Dang, Varun
A1 Wang, Mei
A1 Park, Jung Tak
A1 Deshpande, Supriya
A1 Kadam, Swati
A1 Mardiros, Armen
A1 Zhan, Yumei
A1 Oettgen, Peter
A1 Putta, Sumanth
A1 Yuan, Hang
A1 Lanting, Linda
A1 Natarajan, Rama
YR 2013
UL http://stke.sciencemag.org/content/6/278/ra43.abstract
AB 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.