# Loss of transcriptional homeostasis of genes lacking CpG islands during aging

> **NIH NIH R01** · MOUNT DESERT ISLAND BIOLOGICAL LAB · 2021 · $483,479

## Abstract

PROJECT SUMMARY/ABSTRACT
 Changes in chromatin architecture is a hallmark of aging. Disruption of the nuclear lamina and associated
heterochromatin are commonly observed in various aging contexts, including premature aging diseases, cellular
senescence, and normative aging. Although these shared structural changes have been reported for over two
decades, their impact on transcription and the contribution to age-related degenerative changes remains
unknown. Through computational analysis, we recently identified that CpG islands (CGIs), mammalian
promoter-associated elements, provide important clues to answering this question. In humans, about 60% of
genes contain CGIs at their promoters (CGI+ genes) and are broadly expressed throughout the body, while the
other 40% of genes that do not have CGIs (CGI- genes) exhibit tissue-restricted expression patterns. Our
preliminary results demonstrate that, in young nuclei, only CGI- genes can reside within lamina-associated
heterochromatin, when transcriptionally inactive. This suggests that aging-mediated heterochromatin
decondensation and lamina disruption would specifically hinder the repressive status of CGI- genes. Our data
indeed show over 30% of CGI- genes are mis-activated within various aged tissues, and this pattern coincides
with the loss of organ function. In this project, we will test the novel hypothesis that 1) changes in chromatin
architecture during aging directly trigger uncontrolled expression of CGI- genes in tissues/contexts where they
should not be expressed and this, in turn, 2) accelerates age-associated deterioration. We will also test whether
the 3) pharmacological inhibition of CGI- gene misexpression delay age-related degenerative changes.

## Key facts

- **NIH application ID:** 10209189
- **Project number:** 1R01AG068179-01A1
- **Recipient organization:** MOUNT DESERT ISLAND BIOLOGICAL LAB
- **Principal Investigator:** Samuel Beck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,479
- **Award type:** 1
- **Project period:** 2021-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209189

## Citation

> US National Institutes of Health, RePORTER application 10209189, Loss of transcriptional homeostasis of genes lacking CpG islands during aging (1R01AG068179-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10209189. Licensed CC0.

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