The INO80 chromatin remodeler sustains metabolic stability by promoting TOR signaling and regulating histone acetylation

Abstract

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.

The effect of acetylation on the protein stability of BmApoLp‐III in the silkworm, Bombyx mori

“…Since nonhistone acetylation was first identified, increasingly more functions for acetylation have been found to act on various life processes, including DNA damage response and autophagy (Botrugno et al ., ; Zhong et al ., ; Yasuda et al ., ), genomic stability (Billon et al ., ; Fournier and Tora, ), transcriptional activity (Seo et al ., ), protein degradation (Liu et al ., ; Wei et al ., ) and lysosomal function (Zhang et al ., ). Previous studies have shown that acetylation could compete with ubiquitination at the same lysine residue, thus blocking the ubiquitin‐mediated proteasomal degradation pathway to improve the protein stability, which is involved in cell cycle regulation (Lahusen et al ., ), tumour suppression and progression (Wan et al ., ; Choi et al ., ), bacterial virulence (Sang et al ., ) and signal transduction (Garcia‐Aguilar et al ., ; Beckwith et al ., ; Wei et al ., ). In our previous work, many acetylated sites were found on the nutrient storage proteins in the haemolymph of B. mori , including three storage proteins (SP1, SP2 and SP3), three apolipophorin proteins (BmApoLp‐I, BmApoLp‐II and BmApoLp‐III) and six 30 K proteins (Nie et al ., ).…”

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

“…Recent studies also identified the multi-subunit INO80 and SWI/SNF chromatin remodelers as effectors of ScTORC1 -dependent transcriptional regulation [ 114 , 138 , 139 ], although the link to INO80 is mechanistically best understood. Genetic screens determined that INO80 functionally interacts with the Sc TORC1 pathway, and that it contributes to Sc TORC1-dependent metabolic gene regulation.…”

“…Histone H3 lysine 18 acetylation (H3K18ac) is a histone post-translational modification dependent on active Sc TORC1 signaling [ 117 ], and H3K18ac co-localizes to many Sc TORC1-activated genes. Intriguingly, loss of the Ino80 catalytic subunit reduces H3K18ac at these genes [ 139 ], thus implicating INO80 chromatin remodeling in the regulation of a subset of Sc TORC1-dependent epigenetic modifications. Cells lacking functional INO80 exhibit sustained Sc TORC1 signaling after rapamycin treatment and are more rapamycin-resistant relative to wild-type cells [ 139 ].…”

The Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling

“…These functions reflect the ability of INO80 to shape promoter nucleosome landscape by exchanging histone H2A.Z for H2A in nucleosomes and changing nucleosome positions 1 , 2 . Disruption of INO80 function is associated with cancers 3 – 5 as well as coronary 6 and other vascular diseases 7 . Recently, the structures of fungal and human INO80 complexes bound to nucleosomes were solved using high-resolution cryo-electron microscopy 8 , 9 .…”