%0 Journal Article %J PLoS Biol %D 2022 %T Initiation of wound healing is regulated by the convergence of mechanical and epigenetic cues. %A Bhatt, Tanay %A Dey, Rakesh %A Hegde, Akshay %A Ketkar, Alhad Ashok %A Pulianmackal, Ajai J %A Deb, Ashim P %A Rampalli, Shravanti %A Jamora, Colin %K Biomarkers %K Caspase 8 %K Cues %K Epigenesis, Genetic %K Wound Healing %X

Wound healing in the skin is a complex physiological process that is a product of a cell state transition from homeostasis to repair. Mechanical cues are increasingly being recognized as important regulators of cellular reprogramming, but the mechanism by which it is translated to changes in gene expression and ultimately cellular behavior remains largely a mystery. To probe the molecular underpinnings of this phenomenon further, we used the down-regulation of caspase-8 as a biomarker of a cell entering the wound healing program. We found that the wound-induced release of tension within the epidermis leads to the alteration of gene expression via the nuclear translocation of the DNA methyltransferase 3A (DNMT3a). This enzyme then methylates promoters of genes that are known to be down-regulated in response to wound stimuli as well as potentially novel players in the repair program. Overall, these findings illuminate the convergence of mechanical and epigenetic signaling modules that are important regulators of the transcriptome landscape required to initiate the tissue repair process in the differentiated layers of the epidermis.

%B PLoS Biol %V 20 %P e3001777 %8 2022 09 %G eng %N 9 %R 10.1371/journal.pbio.3001777 %0 Journal Article %J EMBO Rep %D 2019 %T KMT1 family methyltransferases regulate heterochromatin-nuclear periphery tethering via histone and non-histone protein methylation. %A Rao, Radhika Arasala %A Ketkar, Alhad Ashok %A Kedia, Neelam %A Krishnamoorthy, Vignesh K %A Lakshmanan, Vairavan %A Kumar, Pankaj %A Mohanty, Abhishek %A Kumar, Shilpa Dilip %A Raja, Sufi O %A Gulyani, Akash %A Chaturvedi, Chandra Prakash %A Brand, Marjorie %A Palakodeti, Dasaradhi %A Rampalli, Shravanti %X

Euchromatic histone methyltransferases (EHMTs), members of the KMT1 family, 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 methylation. We show that EHMTs methylate and stabilize LaminB1 (LMNB1), which associates with the H3K9me2-marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates heterochromatin anchorage at the NP We further demonstrate that the loss of EHMTs induces many hallmarks of aging including global reduction of H3K27methyl marks and altered nuclear morphology. Consistent with this, we observe a gradual depletion of EHMTs, which correlates with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defects in aged cells. Collectively, our work elucidates a new mechanism by which EHMTs regulate heterochromatin domain organization and reveals their impact on fundamental changes associated with the intrinsic aging process.

%B EMBO Rep %8 2019 Mar 11 %G eng %R 10.15252/embr.201643260