Identification of H3K27me3 binding sites in cerebellar tissue from Atm-/- and / mice

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by ATM -deficiency. We previously identified nuclear accumulation of HDAC4 as a key factor in A-T neurodegeneration of A-T. We report here that polycomb-mediated histone modifications also play plays a role in this process. We find that serine 734 of enhancer-of-Zeste homolog 2 (EZH2) is an ATM kinase target. ATM phosphorylation reduces EZH2 stability thus reducing its histone methylation activity. As a consequence, in A-T patients and Atm / mice, H3K27me3 are is elevated and polycomb repressive complex 2 (PRC2) formation is reduced. ChIP-sequencing shows an increase in H3K27me3 ‘marks’ and a dramatic shift in their location. Shifting marks near several brain-specific genes is consistent with their role in Atm / cell cycle re-entry and cell death. Lentiviral knockdown of EZH2 prevents rescues gene expression and behavioral abnormalities in Atm / mice, suggesting demonstrating that elevated EZH2 is another a novel factor in the neurodegeneration of A T.