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While transcriptional downregulation via PGC-1 and PPAR\u03b1\/ERR\u03b1 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>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 PPAR\u03b1 and ERR\u03b1 but not NF-kB. Sirt1 binding to Sub1 competitively displaced the interaction between Sub1 and GTFs, thereby inhibiting PIC formation at the Sub1-PPAR\u03b1\/ERR\u03b1 complex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag178","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:48:26Z","timestamp":1787226506000},"source":"Crossref","is-referenced-by-count":1,"title":["Sirt1 inhibits the recruitment of RNA polymerase II to metabolic gene promoter during pressure overload through competition with the preinitiation complex on Sub1"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7481-9009","authenticated-orcid":false,"given":"Shin-ichi","family":"Oka","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ 07103 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