Biology subjects

Venkatasubramanian, A.

Publications and source records attributed to Venkatasubramanian, A..

3 recordsLinked to original sources

bioRxiv2026

Restoring Klf9 Expression with Pressure Overload Leads to Metabolic Maladaptation and Early Onset of Heart Failure

Klf9 is a cardiac-enriched transcription factor of the Kruppel-like factor (Klf) family. Klf9 levels decrease during cardiac hypertrophy; however, no studies have examined its transcriptional targets or role in the progression of hypertrophy. Here, we report genome-wide differential Klf9 occupancy during cardiac hypertrophy, with a predominant enrichment at the metabolic gene promoters. Further, using conditional Klf9 knock-in mice subjected to pressure overload for 1 or 2 weeks, we show that restoring Klf9 expression initially inhibits hypertrophy but later leads to early-onset heart failure. We conclude that a decrease in Klf9 is required for metabolic adaptations that support the development of compensatory hypertrophy.

cell biology↗

bioRxiv2025

The Whsc2/NelfA -dependent transcription complex is required for postnatal cardiac development and heart function.

Cardiac malformations and ventricular remodeling due to heart diseases result in compromised cardiac function, eventually leading to heart failure. In this study, we examine the role of cardiac Wolf-Hirschhorn Syndrome candidate 2 (Whsc2), also known as Negative elongation factor A (NELFA), one of the genes encoded in the WHS critical region. The Wolf-Hirschhorn Syndrome is a contiguous genetic disorder due to microdeletions in the critical region, with clinical manifestations of neurological defects frequently associated with congenital malformations, including cardiac defects. NelfA has been implicated in RNA polymerase II (pol II) pausing, suggesting a role in pol II-dependent gene transcription. We previously reported an early onset of heart failure with the acute knockdown of NelfA in hearts undergoing pressure overload-induced cardiac hypertrophy. Here, we characterize a mouse model with cardiomyocyte-specific loss of NelfA function, in which these mice develop spontaneous cardiomyopathy at 2 months of age and exhibit early mortality by 3 months, suggesting a critical role for postnatal NelfA in the heart. Interactome data show that chromatin-bound NelfA interacts with proteins involved in chromatin remodeling (Trim28) and pre-mRNA processing (Adrph1l), along with expected binding partners like RNA pol II, Supt5, and other Nelf proteins. Examination of genomic occupancy of these NelfA-associated proteins in the NelfA knockout (KO) hearts reveals a disassembly of the NelfA nucleated complex at promoters of cardiac-enriched genes, including cytoskeletal and metabolic genes. This deconstruction of the NelfA-dependent complex results in the inhibited expression of these essential genes during postnatal cardiac development, leading to a cardiac contractile and metabolic crisis that precipitates dilated cardiomyopathy.

cell biology↗

bioRxiv2025

Constitutive expression of cardiomyocyte Klf9 precipitates metabolic dysfunction and spontaneous heart failure.

Metabolic adaptations and flexibility during development and disease play an essential in cardiomyocyte function and survival. We recently reported Glucocorticoid receptor (GR)-Kruppel-like factor 9 (Klf9) axis in mediating metabolic adaptations in cardiomyocytes stimulated with Dexamethasone. Klf9 expression decreases in hypertrophic and failing hearts, suggesting its importance in cardiac homeostasis and its potential contribution to dysfunction under pressure overload. Genome wide Klf9 occupancy in adult hearts revealed 2,242 genes directly associated with Klf9, with enrichment in metabolic pathways, autophagy, ubiquitin-mediated proteolysis, and cellular senescence. We generated and characterized a conditional cardiac specific Klf9 knock-In (Klf9KI) mice, which developed progressive cardiac hypertrophy, cardiac dysfunction and cardiac failure by 8wks of age, with mortality by 12-14wks. RNA-seq analysis at 1wk, 4wks, and 8wks showed stage-specific transcriptional changes. At 1 week, 64.81% of differentially expressed genes were downregulated, aligning with Klf9s predicted role as a transcriptional repressor. At 4wks and 8wks, more genes were upregulated, suggesting more of secondary targets in response to cardiac phenotype. KEGG pathway analysis showed dysregulation in lipid, carbohydrate and glutathione metabolism, transcriptional regulation, apoptosis, and innate immunity. Untargeted Metabolomics at 4wks identified significant alterations in tissue metabolite levels, particularly in pathways involving fatty acid metabolism, amino acids, and glucose, correlating with transcriptome data. Mitochondrial function assays revealed progressive dysregulation. At 2 weeks, complex I activity was significantly reduced, while complex II and IV activities were partially preserved. By 4 weeks, all measured respiratory complexes showed significant declines, consistent with decline in mitochondrial function. These mitochondrial deficits preceded overt cardiac dysfunction and likely contributed to the development of hypertrophy and failure. In conclusion, constitutive Klf9 overexpression disrupts transcriptional and metabolic homeostasis, driving progressive hypertrophy, cardiac dysfunction, and failure.

cell biology↗