Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration.

Oriana Lo Re,Manlio Vinciguerra

doi:10.3390/genes8120367

Abstract

Histone variants confer chromatin unique properties. They have specific genomic distribution, regulated by specific deposition and removal machineries. Histone variants, mostly of canonical histones H2A, H2B and H3, have important roles in early embryonic development, in lineage commitment of stem cells, in the converse process of somatic cell reprogramming to pluripotency and, in some cases, in the modulation of animal aging and life span. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Furthermore, macroH2A1 participates in the formation of senescence-associated heterochromatic foci (SAHF) in senescent cells, and multiple lines of evidence in genetically modified mice suggest that macroH2A1 integrates nutritional cues from the extracellular environment to transcriptional programs. Here, we review current molecular evidence based on next generation sequencing data, cell assays and in vivo models supporting different mechanisms that could mediate the function of macroH2A1 in health span and life span. We will further discuss context-dependent and isoform-specific functions. The aim of this review is to provide guidance to assess histone variant macroH2A1 potential as a therapeutic intervention point.

Highlights

The histone family of proteins is highly conserved in eukaryotes
In contrast to the study of Chen et al [36], chromatin immunoprecipitation sequencing uncovered that this escape from senescence in liver cells required activation of transcriptional patterns that were largely independent of the genomic occupancy of macroH2A1 histones [14]
MacroH2A1 variants, in concert with other histone variants, might constitute an important epigenetic mark involved in vertebrate development, and it would be interesting to decipher the reciprocal regulation between macroH2A1 and senescence-associated secretory phenotype (SASP) during normal growth and aging, in absence of oncogenic signals

Summary

Introduction

The histone family of proteins is highly conserved in eukaryotes. DNA is packaged by histones into the nuclei and this is crucial to all DNA-based physical-chemical phenomena. Levels of the splice isoform macroH2A1.1 inversely correlate with proliferation This variant is downregulated in many cancer types, which is associated with poor prognosis [25,26]. In contrast to the study of Chen et al [36], chromatin immunoprecipitation sequencing uncovered that this escape from senescence in liver cells required activation of transcriptional patterns that were largely independent of the genomic occupancy of macroH2A1 histones [14]. These studies suggest macroH2A1 as a novel regulator of oncogene and drug-induced SASP with important implications for disease progression. MacroH2A1 variants, in concert with other histone variants, might constitute an important epigenetic mark involved in vertebrate development, and it would be interesting to decipher the reciprocal regulation between macroH2A1 and SASP during normal growth and aging, in absence of oncogenic signals

MacroH2A1 and Nutrients

MacroH2A1

Findings

Perspectives