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Loganathan, P.

Publications and source records attributed to Loganathan, P..

4 recordsLinked to original sources
bioRxiv2026

Nuclear βactin dependent chromatin accessibility governs stem cell pluripotency and extracellular matrix gene programs to maintain cellular biomechanics for cell lineage decisions

Pluripotency requires coordinated regulation of chromatin state, transcription and extracellular matrix (ECM) mechanics, but how these layers are integrated remains unclear. Here, using {beta}-actin knockout mouse embryonic stem cells (mESCs) and a nuclear-targeted {beta}-actin rescue, we identify nuclear {beta}-actin as a key regulator linking chromatin accessibility to mechanosensitive control of cell fate. {beta}-actin loss reduced OCT4, SOX2 and NANOG, broadly rewired the transcriptome and proteome and decreased accessibility at pluripotency regulatory regions. Integrated RNA-seq and ATAC-seq revealed coordinated dysregulation of stemness, ECM, mechanotransduction and early-lineage programs. These changes were accompanied by fibronectin and collagen upregulation, altered nuclear morphology, reduced Lamin A/C and mechanosensing proteins, increased nuclear YAP1 and greater ECM stiffness heterogeneity. Functionally, knockout cells displayed biased lineage specification, failed neuronal differentiation, ectopic cardiomyocyte-like differentiation, and markedly reduced teratoma growth with diminished ectodermal representation. Nuclear {beta}-actin re-expression restored many molecular, mechanical and differentiation defects, although chromatin rescue remained incomplete. Together, these findings establish nuclear {beta}-actin as an integrator of chromatin regulation and ECM-dependent mechanotransduction that preserves pluripotency and developmental competence.

cell biology↗
bioRxiv2025

Prion protein-derived cell-penetrating peptide inhibits type II diabetes-associated islet amyloid polypeptide aggregation and cytotoxicity

Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone co-packaged and co-secreted with insulin by pancreatic {beta}-cells. A pathological hallmark of type II diabetes is the self-assembly of IAPP into {beta}-sheet rich amyloid fibers, which is associated with {beta}-cell impairment. Previously, we showed that a cell-penetrating peptide (CPP) construct, consisting of a hydrophobic signal sequence coupled to a polycationic nuclear localization signal (NLS)-like sequence, exhibited potent anti-prion activity and antagonism of Alzheimers disease-associated amyloid-{beta} (A{beta}) peptide aggregation and neurotoxicity. Here, we have extended this approach towards type II diabetes by assessing the efficacy of the CPP construct, designated as NCAM1-PrP, in inhibiting IAPP oligomerization, fiber formation and associated cytotoxicity. Using complementary in vitro and in silico experiments, we show that NCAM1-PrP effectively modulates IAPPs toxic structures into non-toxic conformations. This study underlines the potential of our designed CPP-based therapeutic approach as a versatile tool in the battle against amyloid-associated pathologies.

biochemistry↗
bioRxiv2022

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. As part of the nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR and directly affects mitochondrial oxidative phosphorylation (OXPHOS) via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1. NM1 depletion leads to suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae, and redistribution of mitochondria within the cell, which is associated with reduced expression of OXPHOS genes, decreased mitochondrial DNA copy number and deregulated mitochondrial dynamics. This leads to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis and with a metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. We show that NM1 KO cells form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signaling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the early onset of tumorigenesis.

cell biology↗