Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes

Wen-Chuan Hsieh,Benjamin M Sutter,Holly Ruess,Spencer D Barnes,Venkat S Malladi,Benjamin P Tu

doi:10.1016/j.molcel.2021.12.015

Abstract

Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of gene expression with metabolic state. Abundant acetyl-CoA has been linked to the activation of genes involved in cell growth or tumorigenesis through histone acetylation. However, the role of histone acetylation in transcription under low levels of acetyl-CoA remains poorly understood. Here, we use a yeast starvation model to observe the dramatic alteration in the global occupancy of histone acetylation following carbon starvation; the location of histone acetylation marks shifts from growth-promoting genes to gluconeogenic and fat metabolism genes. This reallocation is mediated by both the histone deacetylase Rpd3p and the acetyltransferase Gcn5p, a component of the SAGA transcriptional coactivator. Our findings reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting.

Highlights

To safeguard the genome and precisely regulate its expression, eukaryotic cells utilize histones as the core proteins that packDNA into structural units, enabling its assembly into chromatin (Grunstein, 1990)
Comparing the results from RNA-seq and Chromatin immunoprecipitation (ChIP)-seq experiments, we found that the majority of genes have a positive correlation between the transcriptome and H3K9ac signals under both conditions (Figure 2B), suggesting H3K9ac plays a role in gene activation even upon glucose starvation
To elucidate whether the accumulation of H3 acetylation at gluconeogenic and fat metabolism genes was required for their transcriptional induction, we investigated the responsible histone acetyltransferase (HAT)

Summary

Introduction

To safeguard the genome and precisely regulate its expression, eukaryotic cells utilize histones as the core proteins that packDNA into structural units, enabling its assembly into chromatin (Grunstein, 1990). The first correlations between acetyl-CoA and histone acetylation were revealed through perturbation of metabolic enzymes responsible for the synthesis of acetyl-CoA: acetyl-CoA synthetase (Acs2p) in yeast and ATP citrate lyase (Acly) in mammalian cells (Takahashi et al, 2006; Wellen et al, 2009). Deletion of these enzymes showed that changes in nucleo-cytosolic acetyl-CoA levels can influence bulk histone acetylation, leading to apparent changes in transcription. Our lab has described how acetyl-CoA drives histone acetylation for cell proliferation (Cai et al, 2011); a surge in acetyl-CoA promotes acetylation of histones at growth-promoting genes. This has been observed in some cancer cells to confer a proliferative advantage (Kurdistani, 2007, 2011; Ropero and Esteller, 2007; Seligson et al, 2005)

Objectives

Results

Discussion

Conclusion