Acetyl-CoA Carboxylase Regulates Global Histone Acetylation

Luciano Galdieri,Ales Vancura

doi:10.1074/jbc.m112.380519

Abstract

Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment. However, because nucleocytosolic acetyl-CoA is also used for de novo synthesis of fatty acids, histone acetylation and synthesis of fatty acids compete for the same acetyl-CoA pool. The first and rate-limiting reaction in de novo synthesis of fatty acids is carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by acetyl-CoA carboxylase. In yeast Saccharomyces cerevisiae, acetyl-CoA carboxylase is encoded by the ACC1 gene. In this study, we show that attenuated expression of ACC1 results in increased acetylation of bulk histones, globally increased acetylation of chromatin histones, and altered transcriptional regulation. Together, our data indicate that Acc1p activity regulates the availability of acetyl-CoA for histone acetyltransferases, thus representing a link between intermediary metabolism and epigenetic mechanisms of transcriptional regulation.

Highlights

Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment
To eliminate the possibility that doxycycline affects cell physiology, altering the histone acetylation levels, we investigated the effect of doxycycline on histone acetylation
The major objective of this study was to test the hypothesis that impaired de novo fatty acid synthesis caused by reduced ACC1 expression would increase histone acetylation by increasing the nucleocytosolic pool of acetyl-CoA (Fig. 8)

Summary

Introduction

Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment. Results: Attenuated expression of acetyl-CoA carboxylase, the first and rate-limiting enzyme in de novo fatty acid synthesis, results in increased histone acetylation. Conclusion: Fatty acid biosynthesis competes with histone acetylation for acetyl-CoA. Significance: Intermediary metabolism affects histone acetylation and transcriptional regulation. The first and rate-limiting reaction in de novo synthesis of fatty acids is carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by acetyl-CoA carboxylase. We show that attenuated expression of ACC1 results in increased acetylation of bulk histones, globally increased acetylation of chromatin histones, and altered transcriptional regulation. Our data indicate that Acc1p activity regulates the availability of acetyl-CoA for histone acetyltransferases, representing a link between intermediary metabolism and epigenetic mechanisms of transcriptional regulation

Objectives

Results

Conclusion