Abstract
Aging is the main risk factor for many prevalent diseases. However, the molecular mechanisms regulating aging at the cellular level are largely unknown. Using single cell yeast as a model organism, we found that reducing yeast histone proteins accelerates chronological aging and increasing histone supply extends chronological life span. We sought to identify pathways that regulate chronological life span by controlling intracellular histone levels. Thus, we screened the histone H3/H4 mutant library to uncover histone residues and posttranslational modifications that regulate histone gene expression. We discovered 15 substitution mutations with reduced histone proteins and 5 mutations with increased histone proteins. Among these mutations, we found Set1 complex-catalyzed H3K4me3 promotes histone gene transcription and maintains normal chronological life span. Unlike the canonical functions of H3K4me3 in gene expression, H3K4me3 facilitates histone gene transcription by acting as a boundary to restrict the spread of the repressive HIR/Asf1/Rtt106 complex from histone gene promoters. Collectively, our study identified a novel mechanism by which H3K4me3 antagonizes the HIR/Asf1/Rtt106 repressor complex to promote histone gene expression and extend chronological life span.
Highlights
Aging is the leading risk factor for many human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases [1]
Using the chronological life span assay, we found that hhf1-hht1Δ mutant has shortened life span compared with its wild-type strain (Figure 1A), indicating that similar to the situation in replicative life span, reducing histone protein levels accelerates chronological aging
We found that hir1Δ mutant has extended chronological life span when compared to its wild-type cells (Figure 1B)
Summary
Aging is the leading risk factor for many human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases [1]. The budding yeast Saccharomyces cerevisiae has two different aging models: replicative life span and chronological life span. The replicative life span refers to the number of times a single yeast cell can divide and the chronological life span is the length of time that a postmitotic cell survives. The chronological life span is a good model to study the aging related response and molecular changes within post-mitotic cells [3]. DNA is packaged into chromatin and its fundamental structural unit is the nucleosome. Reduced expression or depletion of core histones during DNA replication disrupts chromatin structure, delays S phase completion and results in mitotic arrest [5,7,8,9]
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