Inhibition of H3K9me3 induces cytoplasmic localization of histone H3 coupled with autophagy

Nucleophagy, or nuclear autophagy, is termed to describe the cellular process of selective autophagic degradation of nuclear components. It was first discovered in yeast; however, the key regulatory gene is not conserved in mammals . Recently a pioneer work linked nucleophagy with senescence in mammalian cells, and the following studies showed that telomere damage is associated with nucleophagy . However, it is largely unknown whether other signals can activate nucleophagy and how the process is controlled in nuclear. Here, we show that inhibition of H3K9me3 by small chemicals induced cytoplasmic localization of histone H3.1 and degradation by autophagy. BIX-01294 treatment also induced cytosolic DNA and activated the cGAS/TBK1 dependent innate immunity pathway, expression of inflammatory genes and autophagic cell death. the deficiency of ATG5/7 enhanced the activation of cGAS pathway. Our study discovered a novel autophagic process selectively degrading nuclear materials in mammalian cells, which is induced by epigenetic dysregulation and coupled with activation of innate immunity pathway and autophagic cell death. Overall design: ChIP-Seq of BIX-treated, SETDB1.KO Cell Lines. RNA-Seq of BIX-treated, ATG5 KD, cGAS KO and SETDB1 KO cell lines.