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

> **NIH NIH P20** · MOUNT DESERT ISLAND BIOLOGICAL LAB · 2021 · $144,606

## 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 
in...

## Key facts

- **NIH application ID:** 10173816
- **Project number:** 5P20GM104318-09
- **Recipient organization:** MOUNT DESERT ISLAND BIOLOGICAL LAB
- **Principal Investigator:** Samuel Beck
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $144,606
- **Award type:** 5
- **Project period:** 2013-09-01 → 2021-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173816

## Citation

> US National Institutes of Health, RePORTER application 10173816, Project 1 - Disruption of CpG island-mediated gene regulation and chromatin architecture in progeria and aging (5P20GM104318-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10173816. Licensed CC0.

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