2026 New Investigator Grant
Tomas Gonzalez Fernandez, Ph.D. Assistant Professor, Department of Bioengineering, Lehigh University
Understanding the Impact of DNA Methylation in Stem Cell Fate and Aging
Abstract
DNA methylation (DNAm) is a key epigenetic mechanism that controls how genes are switched on and off. In stem and progenitor cells, DNAm shapes gene expression by regulating the balance between multipotency and tissue-specific differentiation, and it acts as an epigenetic clock that drives stem cell aging. Understanding this regulation has proven exceptionally difficult, as the human genome contains roughly 28 million sites where methylation can occur. Current techniques for DNAm analysis, such as DNAm arrays, have identified thousands of differentially methylated sites associated with a wide range of cell phenotypes, yet these associations are inherently correlative and cannot establish causation. Experimentally testing the consequences of DNAm in individual sites has likewise remained largely out of reach, since the available chemical tools cause unspecific methylation across the entire genome, and the staggering number of methylation sites makes comprehensive screening with CRISPR-based methylation editors unfeasible. This proposal addresses a fundamental biological question: how does DNA methylation regulate stem cell phenotype during differentiation and aging? To answer it, we will develop a deep learning framework that pinpoints the methylation sites most likely to drive stem cell fate and senescence, and we will then validate their causal roles using CRISPR-based methylation editors capable of adding or removing methylation at specific locations. This work will generate fundamental insights into how site-specific methylation encodes stem cell differentiation and aging, advancing our basic understanding of epigenetic regulation. The integrated computational and experimental framework developed here will serve as a broadly applicable platform for decoding the functional epigenome across diverse biological systems.