The chromatin remodeling factor ISW-1 integrates organismal responses against nuclear and mitochondrial stress

Abstract

Age-associated changes in chromatin structure have a major impact on organismal longevity. Despite being a central part of the ageing process, the organismal responses to the changes in chromatin organization remain unclear. Here we show that moderate disturbance of histone balance during C. elegans development alters histone levels and triggers a stress response associated with increased expression of cytosolic small heat-shock proteins. This stress response is dependent on the transcription factor, HSF-1, and the chromatin remodeling factor, ISW-1. In addition, we show that mitochondrial stress during developmental stages also modulates histone levels, thereby activating a cytosolic stress response similar to that caused by changes in histone balance. These data indicate that histone and mitochondrial perturbations are both monitored through chromatin remodeling and involve the activation of a cytosolic response that affects organismal longevity. HSF-1 and ISW-1 hence emerge as a central mediator of this multi-compartment proteostatic response regulating longevity.

HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity

“…This study unravels an unexpected role of HSB-1/HSF-1 signaling in regulating levels of the core histone protein H4 and its previously unfound functions in modulating the transcription of mitochondrial genome-encoded genes. A recent study has shown that a mild disruption of mitochondrial activity in worms induces an imbalance in the levels of core histone proteins ( 5 ). This leads to elevated protein levels of some, but not all, core histones, increased transcription of HSF-1 target genes, and extension of life span that is dependent on a chromatin remodeling protein, ISW-1 ( 5 ).…”

“…A recent study has shown that a mild disruption of mitochondrial activity in worms induces an imbalance in the levels of core histone proteins ( 5 ). This leads to elevated protein levels of some, but not all, core histones, increased transcription of HSF-1 target genes, and extension of life span that is dependent on a chromatin remodeling protein, ISW-1 ( 5 ). In agreement with these findings, our data also support the requirement of histone H4 in mediating the longevity-promoting effects of impaired mitochondrial function (fig.…”

“…1, D and E , and fig. S2A) ( 5 ), potentially due to the presence of cellular homeostasis mechanisms ( 18 ). Hence, it is likely that many of the biological effects due to H4 RNAi or overexpression might be due to change in levels of multiple core histones and not only of H4.…”

Importance of the Use of Oxidative Stress Biomarkers and Inflammatory Profile in Aqueous and Vitreous Humor in Diabetic Retinopathy

“…This very last is associated to the Base Excision Repair (BER) and the Nucleotide Excision Repair (NER) mechanisms to help repair DNA after an oxidative insult [264]. Chromatin remodeling by its remodeler family SWI/SNF contributes to the response against stress and senescence, at the same time mitochondrial dysfunction induces chromatin remodeling responses [265]. The thioredoxing-interacting protein (TXNIP) is a protein known to have an important impact over OS, inflammation and apoptosis in the pancreas and the retina [266], in recent years it has been considered that these modifications lead to chromatin remodeling in retinal cells.…”

Doxorubicin induces large-scale and differential H2A and H2B redistribution in live cells

“…H2B cytoplasmic accumulation was detected using two different (monoclonal vs. polyclonal) anti-H2B antibodies. Both commercially available antibodies are extensively used to visualize H2B with high specificity and sensitivity [28][29][30]. Nonspecific binding of the secondary antibody was ruled out by incubating the cells with the secondary antibody only (see Fig 2).…”