The INO80 Chromatin Remodeler Sustains Metabolic Stability by Promoting TOR Signaling and Regulating Histone Acetylation

Autor: Egan L Peltan, Alexander P. Paraschuk, Ka Man Wong, Graeme J. Gowans, Ashby J. Morrison, Wei Yao, Sean L. Beckwith, Devin A. King, Laura R. Lee, Tessa L. Eckley, Erin K. Schwartz, Pablo E. García-Nieto
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
Gene Identification and Analysis
Gene Expression
Biochemistry
Histones
0302 clinical medicine
Gene Expression Regulation
Fungal
Homeostasis
Histone code
Genetics (clinical)
Histone Acetyltransferases
Regulation of gene expression
Genetics
0303 health sciences
Chromosome Biology
Organic Compounds
Acetylation
Chromatin
Nucleosomes
3. Good health
Cell biology
Chemistry
Histone
Physical Sciences
Epigenetics
Metabolic Networks and Pathways
Research Article
Saccharomyces cerevisiae Proteins
lcsh:QH426-470
Saccharomyces cerevisiae
Protein Serine-Threonine Kinases
Biology
Genomic Instability
Chromatin remodeling
03 medical and health sciences
Histone H1
Gene Types
DNA-binding proteins
Nucleosome
Gene Regulation
Ino80 complex
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Organisms
Genetically Modified
Ethanol
Organic Chemistry
Chemical Compounds
Biology and Life Sciences
Proteins
Cell Biology
Chromatin Assembly and Disassembly
lcsh:Genetics
030104 developmental biology
Genetic Interactions
Alcohols
biology.protein
Regulator Genes
Protein Processing
Post-Translational
030217 neurology & neurosurgery
Genetic screen
Zdroj: PLoS Genetics, Vol 14, Iss 2, p e1007216 (2018)
PLoS Genetics
Popis: Chromatin remodeling complexes are essential for gene expression programs that coordinate cell function with metabolic status. However, how these remodelers are integrated in metabolic stability pathways is not well known. Here, we report an expansive genetic screen with chromatin remodelers and metabolic regulators in Saccharomyces cerevisiae. We found that, unlike the SWR1 remodeler, the INO80 chromatin remodeling complex is composed of multiple distinct functional subunit modules. We identified a strikingly divergent genetic signature for the Ies6 subunit module that links the INO80 complex to metabolic homeostasis. In particular, mitochondrial maintenance is disrupted in ies6 mutants. INO80 is also needed to communicate TORC1-mediated signaling to chromatin, as ino80 mutants exhibit defective transcriptional profiles and altered histone acetylation of TORC1-responsive genes. Furthermore, comparative analysis reveals subunits of INO80 and mTORC1 have high co-occurrence of alterations in human cancers. Collectively, these results demonstrate that the INO80 complex is a central component of metabolic homeostasis that influences histone acetylation and may contribute to disease when disrupted.
Author summary Cells coordinate their metabolism with the nutrient environment in order to adapt and thrive. One of the key ways that cells regulate their metabolism is through changes in metabolic gene expression. The transcription of genes is often regulated by manipulating chromatin, which is the packaging material of eukaryotic genomes. Chromatin can be dynamically modified by post-translational modifications, such as histone acetylation, and by ATP-dependent chromatin remodeling complexes. We performed an extensive genetic screen in the budding yeast Saccharomyces cerevisiae in order to identify chromatin regulators of cellular metabolism. We found that the INO80 chromatin remodeling complex is required to maintain proper levels of histone acetylation at metabolic genes and is important for the TOR metabolic signaling pathway. Additionally, cancer patients frequently have alterations in both INO80 genes and TOR genes, suggesting that disruption of both these components may facilitate the metabolic aberrations that are a hallmark of many cancer cells.
Databáze: OpenAIRE
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