Abstract
The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis. Acetylation/deacetylation is important for the localization, stability and activation of transcription factors. It remains unknown how Nkx2.5 is deacetylated and how Nkx2.5 acetylation determines its activity. In this study, we provide evidence that the NAD+-dependent class III protein deacetylase SIRT1 deacetylates Nkx2.5 in cardiomyocytes and represses the transcriptional activity of Nkx2.5. We show that SIRT1 interacts with the C-terminus of Nkx2.5 and deacetylates Nkx2.5 at lysine 182 in the homeodomain. The mutation of Nkx2.5 at lysine 182 reduces its transcriptional activity. Furthermore, SIRT1 inhibits the transcriptional activity of Nkx2.5 and represses the expression of its target genes partly by reducing Nkx2.5 binding to its co-factors, including SRF and TBX5. Taken together, these findings demonstrate that SIRT1 deacetylates Nkx2.5 and inhibits the transcriptional activity of Nkx2.5.
Highlights
The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis
We further examined whether endogenous SIRT1 and Nkx2.5 could interact with each other
We isolated and cultured neonatal rat cardiomyocytes (NRCMs) and performed an immunoprecipitation assay with anti-SIRT1 or anti-Nkx2.5 antibodies
Summary
The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis. SIRT1 inhibits the transcriptional activity of Nkx2.5 and represses the expression of its target genes partly by reducing Nkx2.5 binding to its co-factors, including SRF and TBX5. Diverse transcription factors conservatively regulate the functions of cardiomyocytes and their progenitor cells, and participate in cardiac development and homeostasis[1] These transcription factors include Nkx2.5, GATAs, nuclear factor of activated T cells (NFATs), serum response factor (SRF), HAND, TBX and myocyte-specific enhancer-binding factors (MEFs)[2]. They control a cardiac gene program and play a crucial role in transcription regulation during embryogenesis. SIRT1-mediated deacetylation of Nkx2.5 reduces its interaction with its www.nature.com/scientificreports/
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