Year: 2021
Type: article
Abstract: Metabolism-mediated epigenetic changes represent an adapted mechanism for cellular signaling, in which lysine acetylation and methylation have been the historical focus of interest. We recently discovered a β-hydroxybutyrate-mediated epigenetic pathway that couples metabolism to gene expression. However, its regulatory enzymes and substrate proteins remain unknown, hindering its functional study. Here, we report that the acyltransferase p300 can catalyze the enzymatic addition of β-hydroxybutyrate to lysine (Kbhb), while histone deacetylase 1 (HDAC1) and HDAC2 enzymatically remove Kbhb. We demonstrate that p300-dependent histone Kbhb can directly mediate in vitro transcription. Moreover, a comprehensive analysis of Kbhb substrates in mammalian cells has identified 3248 Kbhb sites on 1397 substrate proteins. The dependence of histone Kbhb on p300 argues that enzyme-catalyzed acylation is the major mechanism for nuclear Kbhb. Our study thus reveals key regulatory elements for the Kbhb pathway, laying a foundation for studying its roles in diverse cellular processes.
Source: Science Advances
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Histone Modification Mechanisms and Inhibition, Nuclear Receptor Coactivator Functions and Mechanisms, Systematic screening for new histone marks and studying their epigenetic function, Mechanisms of p53 target gene activation in DNA damage responses, G6317585828, Biochemistry of the lysine beta-hydroxybutyrylation pathway, Protein Acylation and Methylation Mechanisms, G9000108315, Multi-Disciplinary Training Grant in Cancer Research
OpenAlex ID: W3131093652