Functional Analysis of the Novel Histone Variant, H2A.J, in Senescence – H2AJFUN

Cellular senescence contributes to organismal aging. In order to identify novel regulators and biomarkers of cellular senescence, we characterized the chromatin of senescent human fibroblasts by a histone profiling method that we developed (Contrepois et al., 2010, 2012). Remarkably, we observed by mass spectrometry the accumulation of a novel H2A variant called H2A.J (Uniprot Q9BTM1) specifically in the chromatin of cells induced into senescence by persistent DNA damage. H2A.J was present at low levels in proliferating or serum-starved fibroblasts. Like H2A.X, H2A.J contains a phosphorylatable C-terminal SQ motif and is expressed constitutively. In a Nature Communications article that was just published (Contrepois et al., 2017), we showed that knock-down of H2A.J does not affect the entry or the maintenance of senescence in response to DNA damage, but does inhibit the expression of inflammatory genes contributing to the Senescence-Associated Secretory Phenotype (SASP).

Scientific Hypotheses: We suggest that H2A.J might represent a novel biomarker for some types of senescent cells in vivo, and that its action might contribute to the expression of a chronic inflammatory phenotype that is implicated in aging-related diseases.

Objectives: For this project, we would like to address the following questions: 1) How does H2A.J accumulation in senescence promote the expression of inflammatory genes? 2) Which cell types express H2A.J in vivo, and is it a useful biomarker for identifying senescent cells in vivo? 3) Does H2A.J have functions that are distinct from senescence, notably with regards to the immune system ? 4) Does H2A.J contribute to chronic inflammation during aging? These last 2 questions will be addressed with our mouse knock-out model.