MacroH2A1 ChIP-seq from H-RasV12 expressing senescent IMR90 human primary lung fibroblasts

Oncogene induced senescence (OIS) is a tumor suppressive mechanism typified by stable proliferative arrest, a persistent DNA damage response and the senescent-associated secretory phenotype (SASP). MacroH2A1, a tumor suppressive histone variant, is upregulated during OIS. Using ChIP-seq, we found that macroH2A1 undergoes dramatic relocalization during OIS. SASP genes are enriched in macroH2A1-containing chromatin and macroH2A1 is a critical component of the positive feedback loop that maintains SASP expression. Endoplasmic reticulum (ER) stress, a feature of OIS that requires macroH2A1, leads to ATM activation. ER stress triggers a negative feedback loop reducing SASP expression by causing the ATM-dependent removal of macroH2A1 from SASP genes. MacroH2A1 represents a critical control point in the regulation of SASP expression during OIS by We demonstrate that SASP gene expression is regulated by the combined actions of a positive feedback loop that requires macroH2A1 and a negative feedback loop where ER stress leads to ATM activation critical for the removal of macroH2A1 from SASP genes and consequently their repression.