Sirt1 inhibits the recruitment of RNA polymerase II to metabolic gene promoter during pressure overload through competition with the preinitiation complex on Sub1
Abstract
Aims: Heart failure is marked by suppression of fatty acid oxidation (FAO) and mitochondrial ATP production gene expression. While transcriptional downregulation via PGC-1 and PPARα/ERRα has been well documented, the involvement of the general transcriptional machinery remains insufficiently understood. Distinct from its salutary role in many cardiac conditions, endogenous Sirt1 negatively affects cardiac function during pressure overload (PO). This study investigates how Sirt1 modulates preinitiation complex (PIC) assembly and RNA polymerase II (Pol II) recruitment during pathological PO.
Methods and results: Cardiac-specific Sirt1 knock-out (Sirt1 cKO) mice were subjected to PO. Interaction between Sirt1 and Sub1, a protein recruiting GTFs to the gene promoter, was assessed with co-immunoprecipitation, protein pull-down, and molecular docking. Pol II recruitment was evaluated with chromatin immunoprecipitation-sequencing (ChIP-seq) and ChIP-qPCR analyses. The binding affinity of Sirt1 and GTF to the Sub1 GTF binding domain was assessed by immunoprecipitation and protein pull-down assays. Unbiased ChIP-seq and ChIP-qPCR analyses showed that Pol II binding to metabolic gene promoters was downregulated during PO, which was reversed in Sirt1 cKO mice. PO upregulated Sirt1 in the heart and increased its binding to Sub1, which interacts with PPARα and ERRα but not NF-kB. Sirt1 binding to Sub1 competitively displaced the interaction between Sub1 and GTFs, thereby inhibiting PIC formation at the Sub1-PPARα/ERRα complex.
Conclusion: Sirt1 impairs metabolic gene transcription during PO by competitively inhibiting Sub1-mediated recruitment of GTFs and PIC formation. This repression of general transcriptional machinery contributes to the metabolic disturbance and may represent a maladaptive component of the heart failure phenotype.
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BibTeX
@article{oka2026sirt1,
title = {{Sirt1 inhibits the recruitment of RNA polymerase II to metabolic gene promoter during pressure overload through competition with the preinitiation complex on Sub1}},
author = {Shin-ichi Oka and Youssef Mourad and Samta Veera and Peiyong Zhai and Ralph Alcendor and Yunping Guo and Jamie Ades and Sanchita Kashyap and Xiaoyong Xu and Chengchen Hu and Toshihide Kashihara and Takanobu Yamamoto and Yoshiyuki Ikeda and Akihiro Shirakabe and Shohei Ikeda and Wataru Mizushima and Yasuki Nakada and Danish Sayed and Zhi Yang and Maha Abdellatif and Junichi Sadoshima},
journal = {Cardiovascular Research},
year = {2026},
month = aug,
doi = {10.1093/cvr/cvag178},
url = {https://doi.org/10.1093/cvr/cvag178},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sirt1 inhibits the recruitment of RNA polymerase II to metabolic gene promoter during pressure overload through competition with the preinitiation complex on Sub1
AU - Shin-ichi Oka
AU - Youssef Mourad
AU - Samta Veera
AU - Peiyong Zhai
AU - Ralph Alcendor
AU - Yunping Guo
AU - Jamie Ades
AU - Sanchita Kashyap
AU - Xiaoyong Xu
AU - Chengchen Hu
AU - Toshihide Kashihara
AU - Takanobu Yamamoto
AU - Yoshiyuki Ikeda
AU - Akihiro Shirakabe
AU - Shohei Ikeda
AU - Wataru Mizushima
AU - Yasuki Nakada
AU - Danish Sayed
AU - Zhi Yang
AU - Maha Abdellatif
AU - Junichi Sadoshima
PY - 2026
DA - 2026/08/21
JO - Cardiovascular Research
DO - 10.1093/cvr/cvag178
UR - https://doi.org/10.1093/cvr/cvag178
AB - Aims: Heart failure is marked by suppression of fatty acid oxidation (FAO) and mitochondrial ATP production gene expression. While transcriptional downregulation via PGC-1 and PPARα/ERRα has been well documented, the involvement of the general transcriptional machinery remains insufficiently understood. Distinct from its salutary role in many cardiac conditions, endogenous Sirt1 negatively affects cardiac function during pressure overload (PO). This study investigates how Sirt1 modulates preinitiation complex (PIC) assembly and RNA polymerase II (Pol II) recruitment during pathological PO. Methods and results: Cardiac-specific Sirt1 knock-out (Sirt1 cKO) mice were subjected to PO. Interaction between Sirt1 and Sub1, a protein recruiting GTFs to the gene promoter, was assessed with co-immunoprecipitation, protein pull-down, and molecular docking. Pol II recruitment was evaluated with chromatin immunoprecipitation-sequencing (ChIP-seq) and ChIP-qPCR analyses. The binding affinity of Sirt1 and GTF to the Sub1 GTF binding domain was assessed by immunoprecipitation and protein pull-down assays. Unbiased ChIP-seq and ChIP-qPCR analyses showed that Pol II binding to metabolic gene promoters was downregulated during PO, which was reversed in Sirt1 cKO mice. PO upregulated Sirt1 in the heart and increased its binding to Sub1, which interacts with PPARα and ERRα but not NF-kB. Sirt1 binding to Sub1 competitively displaced the interaction between Sub1 and GTFs, thereby inhibiting PIC formation at the Sub1-PPARα/ERRα complex. Conclusion: Sirt1 impairs metabolic gene transcription during PO by competitively inhibiting Sub1-mediated recruitment of GTFs and PIC formation. This repression of general transcriptional machinery contributes to the metabolic disturbance and may represent a maladaptive component of the heart failure phenotype.
SN - 0008-6363
SN - 1755-3245
ER -