Biology subjects

Ivessa, A.

Publications and source records attributed to Ivessa, 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

KAT6A acetylation drives metabolic adaptation to mediate cellular growth and mitochondrial metabolism through AMPK interaction

Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.

cell biology↗