# Genetic and epigenetic architecture of natural telomere length variation

> **NIH NIH R01** · MARSHALL UNIVERSITY · 2022 · $313,466

## Abstract

Project Summary
 Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of
linear eukaryotic chromosomes. Telomeres shorten with age in most human somatic cells, and
their initial length pre-determines cellular lifespan. Mutations in telomere maintenance genes
lead to cancer, premature aging and a number of age-related disorders. While mean telomere
length in humans shows considerable inter-individual variation and appears to be under strong
genetic control, the exact nature of factors establishing telomere length set point remains
elusive. Using the model plant Arabidopsis thaliana, we previously identified several candidate
genes underlying natural telomere length variation in this species. In this proposal, we will utilize
genetic, genomic, biochemical and epigenetic approaches to explore their functions in telomere
length control and other major cellular processes, and to gain an evolutionary perspective on
functional gene pleiotropy. In Aim 1, we will explore several hypotheses for direct and indirect
roles of Arabidopsis TERT gene, which encodes the catalytic subunit of telomerase, in
establishing natural telomere length polymorphism across Arabidopsis genotypes. We will also
employ powerful Arabidopsis genomic and transcriptomic tools to identify and characterize TERT
trans-regulators and uncover novel factors underlying natural variation in telomerase enzyme
activity levels across multiple Arabidopsis genotypes. Through a series of genetic
complementation experiments with Arabidopsis telomere length mutants, experiments in Aim 2
will address the nature and extent of functional redundancies between telomere biology,
ribosome biogenesis and chromatin assembly, and establish the blueprint for dissecting
telomeric versus non-telomeric roles of identified genes. Additionally, in Aim 2 we will utilize
several innovative genomic and epigenetic approaches to identify and validate additional
candidate genes involved in telomere length control. Overall, the results of this study are
expected to significantly increase our understanding of genetic differences underlying telomere
length polymorphism in natural Arabidopsis populations. Because modes of telomere regulation
are highly conserved, our data may also provide novel insight into the molecular basis for
different rates of aging and predisposition to human diseases associated with telomere length
abnormalities.

## Key facts

- **NIH application ID:** 10446527
- **Project number:** 2R01GM127402-06
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** Eugene V Shakirov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $313,466
- **Award type:** 2
- **Project period:** 2018-08-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446527

## Citation

> US National Institutes of Health, RePORTER application 10446527, Genetic and epigenetic architecture of natural telomere length variation (2R01GM127402-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10446527. Licensed CC0.

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