title: TGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.
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.
authors.affiliation: Department of Diabetes and Division of Molecular Diabetes Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. mkato@coh.org
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kato
authors.forename: Varun
authors.initials: V
authors.lastname: Dang
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Jung Tak
authors.initials: JT
authors.lastname: Park
authors.forename: Supriya
authors.initials: S
authors.lastname: Deshpande
authors.forename: Swati
authors.initials: S
authors.lastname: Kadam
authors.forename: Armen
authors.initials: A
authors.lastname: Mardiros
authors.forename: Yumei
authors.initials: Y
authors.lastname: Zhan
authors.forename: Peter
authors.initials: P
authors.lastname: Oettgen
authors.forename: Sumanth
authors.initials: S
authors.lastname: Putta
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D002843:Chromatin; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D016212:Transforming Growth Factor beta