Biology subjects

Rampalli, S.

Publications and source records attributed to Rampalli, S..

4 recordsLinked to original sources

bioRxiv2024

Adipogenic differentiation and inflammatory response is orchestrated by regulating euchromatic histone methyltransferases.

Euchromatic histone methyltransferases (EHMT1/2) play a key role in adipogenesis by regulating gene expression. While the downstream gene functions of EHMTs in adipogenic differentiation have been studied, their regulation and precise individual contributions remain elusive. We discovered the existence of a regulatory mechanism, wherein EHMT1 governs the interdependent expression of itself and the master regulator PPAR during the early phase of adipogenesis. In later stages, EHMT2 levels decline along with reduction in H3K9 dimethylation. Alteration of above sequence of events alone or in the presence of saturated-fatty acids lead to precocious induction of high levels of PPAR, accelerated adipogenesis and hypertrophic adipocytes with a pro-inflammatory phenotype. Countering the decrease in EHMTs effectively abrogated the inflammatory response of the adipocytes. Accordingly, induction of obesity by a high fat diet was sufficient to downregulate H3K9me2 levels and expression of EHMTs along with enhanced IL-6 generation. Taken together, our studies reveal a critical regulatory role played by EHMTs, which coordinates adipogenesis and obesity-induced inflammation.

cell biology↗

bioRxiv2023

Phase Separation of a Novel form of Euchromatic Histone Methyltransferase1 (EHMT1N/C) into cytoplasmic RNA viral Inclusion bodies facilitates their coalescence, thereby enhancing viral replication

Protein lysine methyltransferases (PKMTs) methylate histone and non-histone proteins to regulate biological outcomes such as development and disease including viral infection. While PKMTs have been extensively studied for modulating the antiviral responses via host gene regulation, their role in methylation of proteins encoded by viruses and its impact on host-pathogen interactions remain poorly understood. In this study, we discovered a distinct nucleo-cytoplasmic form of Euchromatic Histone Methyltransferase1(EHMT1N/C), a PKMT, that phase separates into viral inclusion bodies (IBs) upon cytoplasmic RNA-virus infection (Sendai Virus). EHMT1N/C interacts with cytoplasmic EHMT2 and methylates SeV-Nucleoprotein upon infection. Elevated nucleoprotein methylation during infection correlated with coalescence of small IBs into large mature platforms for efficient replication. Inhibition of EHMT activity by pharmacological inhibitors or genetic depletion of EHMT1N/C reduced the size of IBs with a concomitant reduction in replication. Since IB formation is conserved among all cytoplasmic RNA-viruses, our study will have strong implications in understanding the mechanisms regulating IB formation, discerning RNA viral pathogenesis and designing therapeutic strategies.

cell biology↗

bioRxiv2021

The initiation of the wound healing program is regulated by the convergence of mechanical and epigenetic cues

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 downregulation 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 downregulated 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/463764v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1b5b182org.highwire.dtl.DTLVardef@198e646org.highwire.dtl.DTLVardef@1361f4forg.highwire.dtl.DTLVardef@418a84_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2018

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

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 (LaminB1) methylations. We show that EHMTs methylates and stabilizes LaminB1 (LMNB1), which associates with the H3K9me2-marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates the heterochromatin anchorage from the NP. We further demonstrate that the loss of EHMTs induces many hallmarks of aging including global reduction of H3K27methyl marks along with altered nuclear-morphology. Consistent with this, we observed 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 defect 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.

genetics↗