# The Role of 3-Dimensional Genome Integrity In Cardiac Laminopathies

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $518,496

## Abstract

Project Summary
Mutations in the LMNA gene, which encodes type-A lamin proteins that constitute the nuclear lamina network,
cause a broad spectrum of diseases collectively called laminopathies. LMNA is one of the most frequent genes
involved in dilated cardiomyopathy (DCM), an incurable disease characterized arrhythmias and sudden cardiac
death. How mutations in LMNA cause DCM is poorly understood. In the mammalian genome, lamin A interacts
with chromatin in a cell-specific manner at lamina-associated domains (LADs) at the nuclear periphery,
suggesting a key role for lamin A proteins in the overall genome integrity and transcriptional regulation.
However, where and how lamin A interacts with the genome and whether DCM-causing lamin A mutations
rearrange the genome architecture in DCM remains elusive. The central hypothesis of this proposal is that a
subset of LMNA mutations cause DCM through loss of structural function of lamin A, leading to spatial
reorganization of the genome architecture and aberrant gene expression. This hypothesis is based on strong
preliminary data showing that a DCM LMNA mutation causes haploinsufficiency and triggers genome-wide
changes in LADs concomitantly with aberrant gene expression in patient-specific human induced pluripotent
stem cells derived cardiomyocytes (iPSC-CMs). Together our data suggest a mechanistic link between the
dysregulation of genome integrity and the DCM phenotype. The overarching goal of the study is to understand
the molecular etiology responsible for the cardiac-specific phenotypes caused by LMNA mutations and to
demonstrate that impaired lamin A chromatin- and protein-interactions cause DCM. In Aim 1 we will validate
the disruption of the 3D genome reorganization as a causative mechanism of LMNA-related DCM. In Aim 2 we
will decipher the molecular basis of calcium dysregulation and arrhythmia in LMNA DCM, and in Aim 3 we will
develop a therapeutic strategy by modulating the local genome organization. We provided compelling
preliminary data to support the soundness of our hypothesis-driven research proposal. We have assembled a
multidisciplinary team and we are well positioned to achieve the project goals within four years. If successful,
our studies will provide a new paradigm for understanding the pathogenesis and pave the way for targeted
therapies for LMNA-related DCM.

## Key facts

- **NIH application ID:** 10624331
- **Project number:** 5R01HL150414-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ioannis Karakikes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $518,496
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624331

## Citation

> US National Institutes of Health, RePORTER application 10624331, The Role of 3-Dimensional Genome Integrity In Cardiac Laminopathies (5R01HL150414-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10624331. Licensed CC0.

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