Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy

Q: What is the clinical evidence from this study?

Population: LMNA-Cardiomyopathy and Heart Failure. Intervention: Genetic deletion of Kdm5a vs. Active KDM5A (disease model). Primary outcome: Cardiac function and survival.

Q: What does this research mean for the field?

Histone demethylase KDM5A is a pathogenic driver of LMNA-cardiomyopathy whose genetic deletion restores cardiac gene expression, improves heart function, and prolongs survival. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Manisha Deogharia; Chitra Lekha Reddy; Ritapa Chaudhuri; Manogna Sai Chirasani; Abhinav K. Jain; Leila Rouhi; A.J. Marian; Priyatansh Gurha

doi:10.1016/j.jacbts.2026.101714

October 8, 2026JACC Basic to Translational ScienceOpen Access

Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy

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Key result

Kdm5a deletion improves cardiac function and prolongs survival in LMNA-cardiomyopathy mice.

Graphical abstract published by JACC Basic to Translational Science — Graphical abstract · Published by JACC Basic to Translational Science · CC BY-NC-ND 4.0

Why the study?

The chromatin regulators driving epigenetic remodeling in cardiomyocytes during heart failure remain poorly defined.

Does genetic deletion of Kdm5a improve cardiac function and prolong survival in a cardiomyocyte-specific lamin A-deficient mouse model of heart failure?

Key Points

Identify the chromatin regulators driving pathogenic epigenetic remodeling and heart failure in lamin A-deficient cardiomyopathy.
Assessed epigenetic alterations and chromatin regulator activation in a cardiomyocyte-specific lamin A-deficient mouse model.
Profiled promoter histone H3 lysine 4 trimethylation and downstream expression of sarcomeric and mitochondrial metabolic genes.
Engineered genetic deletion of Kdm5a in lamin A-deficient mice to evaluate restoration of gene expression, cardiac function, and overall survival.
KDM5A activation caused widespread redistribution of promoter histone H3 lysine 4 trimethylation, repressing critical sarcomere structure and mitochondrial oxidative metabolism pathways.
Genetic deletion of Kdm5a reversed these epigenetic defects, restored cardiac and metabolic transcriptional programs, improved cardiac function, and significantly prolonged survival.

Structured PICO

Does genetic deletion of Kdm5a improve cardiac function and prolong survival in a cardiomyocyte-specific lamin A-deficient mouse model of heart failure?

P

Population

Cardiomyocyte-specific lamin A-deficient mouse model used to study epigenetic mechanisms of heart failure.

I

Intervention

Genetic deletion of Kdm5a

C

Comparator

Cardiomyocyte-specific lamin A-deficient mice without Kdm5a deletion (implied)

O

Outcome

Histone H3 lysine 4 trimethylation enrichment, reactivation of cardiac and metabolic transcriptional programs, improvement in cardiac function, and survival

Implication

KDM5A-mediated chromatin remodeling is a previously unrecognized epigenetic driver of heart failure in LMNA-cardiomyopathy, and its deletion improves cardiac function and survival in mice.

Abstract

Heart failure is associated with widespread epigenetic remodeling in cardiomyocytes, but the chromatin regulators driving this process remain poorly defined. We identify the histone H3K4 demethylase KDM5A as a key epigenetic mediator of heart failure in a cardiomyocyte-specific lamin A-deficient mouse model. Disease-associated activation of KDM5A leads to redistribution of promoter histone H3 lysine 4 trimethylation and repression of genes regulating sarcomere structure and mitochondrial oxidative metabolism. Genetic deletion of Kdm5a restores histone H3 lysine 4 trimethylation enrichment, reactivates cardiac and metabolic transcriptional programs, improves cardiac function, and prolongs survival. These findings identify KDM5A-mediated chromatin remodeling as a previously unrecognized mechanism of heart failure and highlight KDM5A as a potential therapeutic target.

Discussion

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Cite This Study

Deogharia et al. (2026) studied LMNA-Cardiomyopathy and Heart Failure. Genetic deletion of Kdm5a vs. Active KDM5A (disease model) was evaluated on Cardiac function and survival. Genetic deletion of Kdm5a in a mouse model of LMNA-cardiomyopathy improved cardiac function and prolonged survival by restoring histone H3 lysine 4 trimethylation and reactivating transcriptional programs.

synapsesocial.com/papers/6ac98744a26deea15a5121a7 https://doi.org/10.1016/j.jacbts.2026.101714

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Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

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