# Mechanisms in Lamin A function in gene regulation

> **NIH NIH R33** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $617,899

## Abstract

PROJECT SUMMARY
Lamin A is a vertebrate-specific nuclear lamina component that has been implicated in a variety of cellular
functions, including structural integrity of the nucleus, sensing mechanical stress, cell signaling, and chromatin
organization. Point mutations in Lamin A cause a spectrum of human degenerative disorders collectively called
laminopathies including muscular dystrophies, cardiomyopathies, and a multisystem disorder known as
progeria. Despite intense study, the mechanisms by which Lamin A affects cellular processes and causes such
striking and tissue-specific human disease phenotypes remain unclear. The central hypothesis of this project is
that Lamin A functions in part as a transcription factor, specifically as a positive modulator of enhancer
function. This is a new way of thinking about Lamin A function. This hypothesis is based on strong preliminary
data, showing that Lamin A associates with gene promoters and enhancers in human fibroblasts and that gains
and losses of Lamin A-enhancer interactions were accompanied respectively by up-regulation and down-
regulation of nearby genes. The overall objective of this proposed research is to rigorously test the hypothesis
that Lamin A acts as an transcriptional activator at gene regulatory regions in the mammalian genome. The
aim of the R21 phase is to identify the cell-cycle stages and cell types in which Lamin A associates with gene
regulatory regions and to verify that Lamin A acts as transcription regulator. The R33 phase will probe the
mechanism and function of Lamin A-enhancer associations. Specifically, this phase will focus on identifying
proteins interacting with Lamin A at regulatory regions, identifying subnuclear localization of Lamin A important
for the associations and function, and investigating the contribution of Lamin A-chromatin interactions to
development of laminopathy-related cardiovascular disease. Altogether, the project aims to prove that Lamin A
acts as a transcription activator in the mammalian genome. If proven, this entirely new mechanism of action
will open new research avenues to understanding vertebrate-specific mechanisms of gene regulation and the
function of Lamin A in normal physiological processes and disease. It would also provide insights to the
evolution of Lamin A and the biochemical properties that allow it to act as both an intermediate filament and a
factor used in gene regulation. The experiments proposed would test a hypothesis that offers a direct and
logical mechanistic explanation for the molecular and physical phenotypes of laminopathies.

## Key facts

- **NIH application ID:** 10152508
- **Project number:** 7R33AG054770-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kohta Ikegami
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $617,899
- **Award type:** 7
- **Project period:** 2017-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152508

## Citation

> US National Institutes of Health, RePORTER application 10152508, Mechanisms in Lamin A function in gene regulation (7R33AG054770-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152508. Licensed CC0.

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