Biological Sciences Division
Published August 15, 2025 | Version v1
Journal article Metadata-only

ACSS2 coupled with KAT7 regulates histone β-hydroxybutyrylation to enhance transcription

Creators

  • 1. Tianjin Medical University
  • 2. University of Chicago

Description

Histone lysine β-hydroxybutyrylation (Kbhb) is an epigenetic mark linking ketone metabolism to transcription. However, the molecular mechanism by which β-hydroxybutyrate is converted to β-hydroxybutyryl–coenzyme A (BHB-CoA), the cofactor for Kbhb, remains unknown. Here, we report that acetyl-CoA synthetase short-chain family member 2 (ACSS2) coupled with lysine acetyltransferase 7 (KAT7) modulates β-hydroxybutyrylation on lysine 9 of histone H3 (H3K9bhb) to promote transcription. We show that KAT7 serves as a β-hydroxybutyryltransferase and preferably catalyzes histone Kbhb, especially H3K9bhb, in 1171 identified Kbhb substrates. ACSS2 is a BHB-CoA synthetase. This enzyme can sense cellular β-hydroxybutyrate and translocate into the nucleus, where it binds to and colocalizes with KAT7 at specific locus of chromatin. The ACSS2-generated BHB-CoA can fuel KAT7 for histone H3K9bhb. We demonstrate that the β-hydroxybutyrate drives the ACSS2-KAT7-H3K9bhb axis to promote epigenetic regulation and tumor cell growth. Our study not only identifies the founding member of BHB-CoA ligase but also reveals the mechanism underlying KAT7-catalyzed histone Kbhb using ACSS2-generated BHB-CoA.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD051685, PXD051668, and PXD051692. Raw data of CUT&Tag and RNA-seq can be obtained at the Gene Expression Omnibus database under accession nos. GSE267130 (CUT&Tag) and GSE267129 (RNA-seq).

Additional details

Identifiers

DOI
10.1126/sciadv.adv8448
Other
oai:uchicago.tind.io:16196

Funding

National Natural Science Foundation of China
22274114
National Natural Science Foundation of China
22374106
National Natural Science Foundation of China
22474090
Tianjin Medical University
Talent Excellence Program

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research