Biology subjects

Deogharia, M.

Publications and source records attributed to Deogharia, M..

3 recordsLinked to original sources

bioRxiv2026

The Epigenetic Regulator Histone Demethylase KDM5A is Activated and Pathogenic in a Mouse Model of Heart Failure

Heart failure is a complex disease characterized by the dysregulation of gene expression that culminates in cardiac dysfunction. Epigenetic regulators play a critical role in control of transcription and are increasingly implicated in the pathogenesis of heart failure. We recently showed that the histone demethylase KDM5A is reactivated in the heart of human patients and mouse models of heart failure. However, its pathogenic role in heart failure remained unknown. Utilizing a mouse model of heart failure caused by the deletion of the Lmna gene in cardiomyocytes and referred to as LMNA-cardiomyopathy (LMNA-CMP), we show that KDM5A is activated, and expression levels of genes involved in myocyte structure and function, including oxidative phosphorylation (OXPHOS), are suppressed. To determine the pathogenic role of KDM5A in heart failure, the Kdm5a gene was specifically deleted in cardiomyocytes in LMNA-CMP mice (Myh6-Cre:LmnaF/F:Kdm5aF/F). The deletion of the Kdm5a gene improved cardiac function, prolonged survival, attenuated fibrosis, and reduced cell death in LMNA-CMP mice. Transcriptome analysis showed that the deletion of the Kdm5a gene restored the expression of over 1,400 dysregulated genes, including those involved in fatty acid metabolism, myogenesis, and OXPHOS in the Myh6-Cre:LmnaF/F:Kdm5aF/F mice. Genome-wide profiling of the epigenetic histone mark H3 lysine 4 trimethylation (H3K4me3), the main target of KDM5A, by CUT&RUN assay showed that deletion of the Kdm5a gene partially restored H3K4me3 deposits at loci encoding cardiac transcription factors and metabolic regulators, including Tbx5 and Esrrg, with concomitant rescue of their downstream targets. These findings identify KDM5A as a key epigenetic regulator of cardiomyocyte gene expression and uncover a mechanistic role for KDM5A in the pathogenesis of heart failure.

genetics↗

bioRxiv2025

Intrinsically Disordered Regions Form Nucleoli and Cajal Bodies While Fostering RNA Modification

One of the densest compartments in the cell is the dense fibrillar component (DFC) of the nucleolus, consisting mainly of nascent ribosomal RNA (rRNA), small nucleolar ribonucleoproteins (snoRNPs) and their chaperone Nopp140. How this biomolecular condensate is formed and what underlies its structure is poorly understood like that of most liquid-liquid phase separated condensates. Although we established that Nopp140 is important for the cohesiveness of the DFC and for rRNA modification, it is not known how this is achieved. Here we demonstrate that Nopp140 concentrates intrinsically disordered and nuclear localization signal (NLS)-rich protein regions (IDRs), including a newly identified RNA polymerase I C-terminal domain (CTD) of the RNA polymerase I associated factor PAF49. Altogether, this network forms the DFC, a liquid-liquid phase separated biomolecular condensate that fosters rRNA modification. This mechanism ensures near 100 percent modification efficiency at some 200 nucleotides in every one of the 10 million or so rRNAs per cell.

cell biology↗

bioRxiv2023

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization

RationaleHuman pluripotent stem cell-derived CMs (iPSC-CMs) are a valuable tool for disease modeling, cell therapy and to reconstruct the CM maturation process and identify, characterize factors that regulate maturation. The transition from immature fetal to adult CM entails coordinated regulation of the mature gene programming, which is characterized by the induction of myofilament and OXPHOS gene expression among others. Recent studies in Drosophila, C. elegans, and C2C12 myoblast cell lines have implicated the histone H3K4me3 demethylase KDM5 and its homologs, as a potential regulator of developmental gene program and mitochondrial function. We speculated that KDM5 may potentiate the maturation of iPSC-CMs by targeting a conserved epigenetic program that encompass mitochondrial OXPHOS and other CM specific maturation genes. ObjectivesThe purpose of this study is to determine the role of KDM5 in iPSC-CM maturation. Methods and ResultsImmunoblot analysis revealed that KDM5A, B, and C expression was progressively downregulated in postnatal cardiomyocytes and absent in adult hearts and CMs. Additionally, KDM5 proteins were found to be persistently expressed in iPSC-CMs up to 60 days after the onset of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor-resulted in differential regulation of 2,372 genes including upregulation of Fatty acid oxidation (FAO), OXPHOS, and myogenic gene programs in iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN assay revealed enriched H3K4me3 peaks at the promoter regions of FAO, OXPHOS, and sarcomere genes. Consistent with the chromatin and gene expression data, KDM5 inhibition led to increased expression of multiple sarcomere proteins, enhanced myofibrillar organization and improved calcium handling. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene, which is known to regulate OXPHOS and cardiomyocyte maturation, and resulted in its increased RNA and protein levels. Finally, KDM5 inhibition increased baseline, peak, and spare oxygen consumption rates in iPSC-CMs. ConclusionsKDM5 regulates the maturation of iPSC-CMs by epigenetically regulating the expression of ESRRA, OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.

genomics↗