Biology subjects

Vemula, P.

Publications and source records attributed to Vemula, P..

3 recordsLinked to original sources

bioRxiv2025

Single-cell transcriptomics reveal ddx43+ cells as regulators of slow-cycling neoblasts in planaria

Cell cycle dynamics are fundamental to stem cell maintenance and differentiation. While the G1 phase is known to influence stem cell fate decisions, the mechanisms regulating its duration remain poorly understood. Using Schmidtea mediterranea, a highly tractable model for studying regeneration, we uncovered how the interplay of systemic and local cues from specialized cell types regulates G1 phase progression, thereby priming the cells in a slow-cycling state poised to differentiate. Single-cell transcriptomics identified G1-enriched, non-committed neoblasts that give rise to a previously uncharacterized ddx43 cell type, localized near sub-epidermal muscle and closely associated with surrounding neoblasts. Functional analyses revealed that ddx43 cells act as gatekeepers, maintaining adjacent neoblasts in an extended G1 phase and a differentiation-primed state. ddx43 knockdown led to neoblast hyperproliferation, highlighting their niche-like regulatory role. Following injury, extracellular signal-regulated kinase (Erk) signalling that propagates to distal regions via subepidermal muscle cells is critical for suppression of ddx43 cells by downregulating Notch signalling. This establishes a critical cross-talk between sub-epidermal muscle and ddx43 cells, mediated by the Erk-Notch axis, essential for maintaining G1 phase extension. In summary, we reveal a ddx43-dependent, non-cell autonomous mechanism that regulates a transient, slow-cycling neoblast population, offering new insights into how extrinsic cues orchestrate stem cell cycling during tissue homeostasis and regeneration.

developmental 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↗

bioRxiv2022

Evaluating the efficacy of commercially available antisense oligonucleotides to reduce mouse and human tau in vivo

Tauopathies, including Alzheimers disease (AD), are neurodegenerative diseases characterized by the accumulation of tau protein encoded by the MAPT (Microtubule Associated Protein Tau) gene. Various strategies targeting mechanisms to reduce tau pathology have been proposed and several tau-directed therapies are being investigated in clinical trials. Our lab previously developed a novel strategy to lower tau protein levels using antisense oligonucleotides (ASOs), showing that human tau (hTau) reduction in aged PS19 tauopathy mice reversed phosphorylated tau pathology, spared neurons, and prolonged survival. Currently, the tau-lowering ASO is being evaluated in the clinical trials with successful phase 1b results. Similarly, preclinical and clinical studies have demonstrated the use of other ASOs as effective therapeutic strategies. Acquiring ASOs for research purposes may be limited by partnerships with pharmaceutical companies. However, ASOs can be obtained through commercial vendors. The current study evaluates the efficacy of mouse and human tau-targeting ASOs obtained from a commercial vendor in various mouse models. We show that mice treated with purchased ASOs distribute among various brain cell types including neurons, microglia, and astrocytes. Mice treated with tau lowering ASOs show decreased mouse or human tau mRNA and protein levels. In addition, human tau lowering ASO-treated PS19 mice showed decreased phosphorylated tau (AT8) and gliosis relative to saline-treated PS19 mice. The results obtained in PS19 mice are consistent with data obtained from our previous study using a non-commercial tau-lowering ASO. Overall, the present study demonstrates the efficacy of commercially-available tau targeting ASOs in vivo to support their broad use by researchers.

neuroscience↗