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Histone malonylation is regulated by SIRT5 and KAT2A
Ran Zhang1, Joanna Bons1, Grace Scheidemantle2
1Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Iscience
|March 7, 2023
Summary
Histone malonylation, a protein modification, is regulated by malonyl-co-enzyme A availability and the deacylase SIRT5. This modification impacts ribosomal gene expression and increases with age.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- Lysine malonylation is a posttranslational modification found in proteins, including histones.
- The regulation and functional relevance of histone malonylation remain largely unknown.
Purpose of the Study:
- To investigate the regulation and functional significance of histone malonylation.
- To identify enzymes involved in catalyzing histone malonylation.
- To explore the role of histone malonylation in gene expression.
Main Methods:
- Investigated the effect of malonyl-co-enzyme A availability on lysine malonylation.
- Assessed the role of the deacylase SIRT5 in regulating histone malonylation.
- Performed knockdown of lysine acetyltransferases (KATs) to identify potential malonyltransferases.
- Utilized mass spectrometry to identify malonylated histone sites.
- Examined the localization of acetyl-CoA carboxylase (ACC) and its relationship with histone malonylation and ribosomal RNA expression.
- Compared global lysine malonylation and ACC expression in young versus aged mouse brains.
Main Results:
- Malonylation of histones is influenced by malonyl-co-enzyme A availability and is reduced by SIRT5.
- KAT2A knockdown significantly decreased histone malonylation.
- H2B_K5 was identified as a highly malonylated site regulated by SIRT5 in mouse tissues.
- Acetyl-CoA carboxylase (ACC) localizes to the nucleolus, and histone malonylation correlates with increased nucleolar area and ribosomal RNA expression.
- Global lysine malonylation and ACC expression are elevated in older mouse brains.
Conclusions:
- Histone malonylation is a regulated process influenced by malonyl-CoA levels and SIRT5.
- KAT2A is implicated in catalyzing histone malonylation.
- Histone malonylation plays a role in regulating ribosomal gene expression.
- Increased histone malonylation and ACC expression in aged brains suggest a potential link to aging processes.
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