# Project 1 - Disruption of CpG island-mediated gene regulation and chromatin architecture in progeria and aging

> **NIH NIH P20** · MOUNT DESERT ISLAND BIOLOGICAL LAB · 2020 · $329,173

## Abstract

PROJECT 1 (Beck) PROJECT SUMMARY
 Aging is an inevitable and natural process of life that is characterized by impaired body functions and
increased susceptibility to both physical and mental disease. Age-related disease has grown into a major
societal and economic problem as life expectancy continues to increase. Developing therapies that delay the
onset of age-related disease represents a pressing biomedical research and public health need.
 Progeria is caused by a rare de novo mutation in the lamin A gene. Lamin A is a structural protein in
the nuclear lamina that functions to tether transcriptionally inactive heterochromatin to the nuclear
periphery. The symptoms of progeria mimic various age-related pathologies, including vision loss,
musculoskeletal degeneration, liver steatosis, atherosclerosis, hair loss and hardened skin. Progeria thus
provides a unique model for understanding the biology of aging.
 Despite the known molecular cause of progeria, the exact biological mechanism of how a mutation in
lamin A gives rise to aging-like symptoms in various tissues is not understood. Using computational
approaches, we identified a unique link between lamin and CpG islands (CGIs). CGIs are DNA elements with
unusually high frequencies of the Cytosine-phosphate-Guanine dinucleotide that are primarily associated with
gene promoters. Our results demonstrate that silent genes lacking CGIs (CGI-) form heterochromatin and
localize to the nuclear periphery, and that lamin proteins interact primarily with the promoters of silent
CGI- genes. Genes containing CGIs (CGI+) associate primarily with euchromatin, even when silent.
 A growing body of evidence suggests that aging-associated changes in nuclear lamina and chromatin
architecture disrupt gene regulation that leads to tissue-specific degenerative disease. The overarching goal
of this proposal is to begin defining how lamin A regulates gene expression. We will test the hypothesis
that the progeria lamin A mutation selectively disrupts CGI- gene regulation in a tissue-specific manner using a
unique resource, progeria patient iPS cells. Gene expression and cellular abnormalities associated with
progeria and aging will be characterized in normal and progeria iPS cells differentiated into cardiomyocytes
and hepatocytes. We will also characterize gene regulation and cellular properties in differentiated normal and
progeria iPS cells into which we have introduced or corrected the progeria lamin A mutation using CRISPR-
Cas9 genome editing. Finally, we will conduct a large-scale meta-analysis of publicly-available genome-scale
datasets generated under different aging contexts to determine if the expression and epigenetic regulation of
CGI- genes is selectively disrupted during aging.
 The studies we propose uniquely analyze gene regulation and chromatin architecture from the
perspective of CGI elements, which are often overlooked. Our studies will thus provide new and fundamental
insights into progeria, aging, a...

## Key facts

- **NIH application ID:** 9937747
- **Project number:** 5P20GM104318-08
- **Recipient organization:** MOUNT DESERT ISLAND BIOLOGICAL LAB
- **Principal Investigator:** Samuel Beck
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,173
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937747

## Citation

> US National Institutes of Health, RePORTER application 9937747, Project 1 - Disruption of CpG island-mediated gene regulation and chromatin architecture in progeria and aging (5P20GM104318-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937747. Licensed CC0.

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