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

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.

Fine Chromatin-Driven Mechanism of Transcription Interference by Antisense Noncoding Transcription

“…Similarly, such nucleosome movements are observed upon gene activation during the metabolic cycle when gene expression is synchronized (Nocetti and Whitehouse, 2016). In agreement with our model, gene expression is maximal when À1/+1 nucleosomes are pushed aside in a movement mainly driven by H3K9ac and H3K18ac modifications (Hughes et al, 2012;Nocetti and Whitehouse, 2016;Sá nchez-Gaya et al, 2018;Weiner et al, 2010).…”

Fine chromatin-driven mechanism of transcription interference by antisense noncoding transcription

“…Similarly, such nucleosome movements are observed upon gene activation during the metabolic cycle when gene expression is synchronized(Nocetti and Whitehouse 2016). In agreement with our model, gene expression is maximal when -1/+1 nucleosomes are pushed aside in a movement mainly driven by H3K9ac and H3K18ac modifications(Weiner et al 2010;Hughes et al 2012;Nocetti and Whitehouse 2016;Sanchez-Gaya et al 2018).…”

Transcriptional changes are regulated by metabolic pathway dynamics but decoupled from protein levels

“…One intriguing possibility is that transcription may have additional roles in cellular physiology, aside from RNA synthesis. Transcription and the chromatin environment are deeply intertwined and extensively remodel one another (Kouzarides, 2007;Skalska et al, 2017). Furthermore, both processes are directly controlled by metabolism as certain core metabolic enzymes such as Hxk2p, and kinases such as TOR, can bind to the DNA via transcription factors and regulate promoter activity (Ahuatzi et al, 2007;Herrero et al, 1998;Tsang et al, 2010;Vega et al, 2016).…”

“…In this study we perform a multiomics analysis (Sanchez-Gaya et al, 2018) of the YMC, from the level of transcription through to the proteome. In the process, we reveal that protein turnover rates can completely attenuate cycling transcription and that transcriptional changes are often the consequence, rather than the cause, of changes in cellular physiology.…”