Elucidating the Role of Chromatin State and Transcription Factors on the Regulation of the Yeast Metabolic Cycle: A Multi-Omic Integrative Approach.

Víctor Sánchez-Gaya,Salvador Casaní-Galdón,Ana Conesa,Jane Mellor,Zheng Kuang,Manuel Ugidos,Sonia Tarazona

doi:10.3389/fgene.2018.00578

Abstract

The Yeast Metabolic Cycle (YMC) is a model system in which levels of around 60% of the yeast transcripts cycle over time. The spatial and temporal resolution provided by the YMC has revealed that changes in the yeast metabolic landscape and chromatin status can be related to cycling gene expression. However, the interplay between histone modifications and transcription factor activity during the YMC is still poorly understood. Here we apply an innovative statistical approach to integrate chromatin state (ChIP-seq) and gene expression (RNA-seq) data to investigate the transcriptional control during the YMC. By using the multivariate regression models N-PLS (Partial Least Squares) and MORE (Multi-Omics REgulation) methodologies, we assessed the contribution of histone marks and transcription factors to the regulation of gene expression in the YMC. We found that H3K18ac and H3K9ac were the most important histone modifications, whereas Sfp1, Hfi1, Pip2, Mig2, and Yhp1 emerged as the most relevant transcription factors. A significant association in the co-regulation of gene expression was found between H3K18ac and the transcription factors Pip2 (involved in fatty acids metabolism), Xbp1 (cyclin implicated in the regulation of carbohydrate and amino acid metabolism), and Hfi1 (involved in the formation of the SAGA complex). These results evidence the crucial role of histone lysine acetylation levels in the regulation of gene expression in the YMC through the coordinated action of transcription factors and lysine acetyltransferases.

Highlights

The Yeast Metabolic Cycle (YMC) is defined by robust periodic oscillations of gene expression that appear in continuous culture systems under aerobic glucose-limited conditions
Our results revealed the impact of the different histone modifications on YMC progress and pointed out different transcription factors (TFs) that might contribute to the molecular regulation of the cycle
Little is still known about the regulatory effect of histone modifications on gene expression in the YMC

Summary

Introduction

The Yeast Metabolic Cycle (YMC) is defined by robust periodic oscillations of gene expression that appear in continuous culture systems under aerobic glucose-limited conditions. The RB phase was first defined as a reductive phase (Tu et al, 2005), but recent works (Murray et al, 2007; Mellor, 2016) have highlighted its oxidative state and proposed it to be part of the HOC phase Functional profiling of these phases revealed an orchestration of gene expression, which fluctuates in response to environmental conditions, drives the cellular physiological changes and prepares the molecular mechanisms necessary for cycling. Metabolomics studies have shown that metabolite profiles follow a periodic cycle across the YMC (Tu et al, 2007; Mohler et al, 2008), highlighting their importance in enzymatic allosteric regulation and synchronization of yeast ultradian rhythms (Mellor, 2016)

Methods

Results

Conclusion