Euchromatic histone methyltransferases regulate peripheral heterochromatin tethering via histone and non-histone protein methylations

Euchromatic histone methyltransferases (EHMTs) methylate histone and non-histone proteins. Here we uncover a novel role for EHMTs in regulating heterochromatin anchorage to the nuclear periphery (NP) via non-histone methylations. In search for mechanism, we identified EHMTs methylate LaminB1 (LMNB1) that associates with the H3K9me2 marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates the heterochromatin anchorage from the nuclear periphery. We further demonstrate that the loss of EHMTs induced many hallmarks of aging including global reduction of H3K27 methyl marks along with altered nuclear-morphology. Keeping consistent with this, we observed gradual depletion of EHMTs, which correlated with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defect in aged cells. Collectively our studies elucidated a new mechanism by which EHMTs regulate heterochromatin domain organization and explains its impact on fundamental changes associated with the intrinsic aging process.