Differential binding of EHMT1,H3k9me2,LMNB1 in fetal Vs adult fibroblast

Perinuclear heterochromatin is an emerging nuclear domain for driving many normal and disease processes, including development, cancer and aging. Here we uncover a novel role for Euchromatic histone methyltransferases 1 in tethering heterochromatin to the nuclear periphery (NP). Surprisingly, depletion of EHMT1 was sufficient to release heterochromatin from the periphery. In search for the mechanism, we identified that the EHMT1 regulates factors critical for heterochromatin organization and stability of laminB1 via its methylation, thereby regulating higher order chromatin organization at the NP. Loss of EHMT1 induced many hallmarks of aging including global reduction of H3K27me2/3 marks along with altered nuclear morphology. Keeping consistent with this, we observed gradual loss of EHMT1 and methylated LMNB1 in aging human fibroblasts. Collectively our studies elucidated a new mechanism by which EHMT1 regulate heterochromatin domain organization and explains its impact on fundamental changes associated with the intrinsic aging process.

核周异染色质（perinuclear heterochromatin）是一类新兴核结构域，参与调控发育、癌症及衰老等诸多正常生理与疾病进程。本研究首次揭示了常染色质组蛋白甲基转移酶1（Euchromatic histone methyltransferases 1，EHMT1）在将异染色质锚定至核周（nuclear periphery, NP）过程中的全新功能。令人意外的是，仅耗竭EHMT1即可促使异染色质从核周解离。为探究其分子机制，我们发现EHMT1可通过自身的甲基化修饰，调控异染色质组织的关键因子以及核纤层蛋白B1（lamin B1）的稳定性，进而调控核周区域的高级染色质结构。EHMT1的缺失会诱导诸多衰老标志性特征，包括H3K27me2/3修饰的整体水平显著降低，同时伴随核形态异常。与此一致的是，我们在衰老的人成纤维细胞中观察到EHMT1与甲基化核纤层蛋白B1的水平随衰老逐渐下降。综上，本研究阐明了EHMT1调控异染色质结构域组织的全新机制，并解释了其在介导内在衰老进程相关根本性改变中的作用。