# Epigenetic Regulation of Lineage Specification

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $378,288

## Abstract

PROJECT ABSTRACT
My lab is focused on the epigenetic and transcriptional regulation of lineage specification. In multicellular
organisms all cells share the same genome, however different cell types acquire distinct features and perform
specialized functions. During the process of lineage specification, multipotent precursor cells give rise to progeny
cells with specialized, characteristic patterns of gene expression. Perturbations in the process of lineage
specification can result in human disorders, such as malignancies and developmental syndromes. Thus, by
uncovering the fundamental principles that ensure robust coordination of cell fate progression we can learn how
to better address diseases wherein that coordination is compromised. Lineage-specifying transcription factors
drive cell-specific gene expression programs, but their access to the DNA is finely tuned by epigenetic machinery
that regulate DNA methylation and histone modifications. Importantly, lineage-specifying transcription factors
cannot bind to methylated cytosines in DNA. A fundamental step in the establishment of cell fate is the unmasking
of specific transcription factor binding sites by targeted removal of methylated cytosines. This process is tightly
regulated by the Ten Eleven Translocation (TET) family of proteins that share a catalytic domain and can oxidize
5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC) and other oxidized cytosines. Each
modified cytosine is a stable epigenetic mark that can be preferentially recognized by transcription factors. In a
given cell type there can be simultaneous expression of at least two of the three TET family members. Though
the function of each protein is obscure, our previous research revealed an instrumental role of TET proteins in
fine-tuning the expression of lineage specification factors and ensuring proper cell-maturation, by tight control of
cell proliferation. We hypothesize that TET proteins act in concert with largely unknown, cell-specific, factors that
mediate their recruitment to the DNA. In progenitor cells, these pioneer factors anchor TET proteins to specific
loci. Then TET proteins initiate the process of 5mC oxidization, allowing for orchestrated recruitment of lineage
specifying transcription factors. The overarching mission of our research is to decipher the TET mediated
mechanisms that regulate cell lineage choice and specification. We will utilize genomic, genetic and biochemical
approaches to investigate changes in modified cytosine (5hmC), chromatin accessibility, and gene expression
to: 1) dissect the shared versus the distinct functions of TET proteins; 2) determine whether TET proteins function
through canonical, catalytic-dependent activities or have additional, unexpected, catalytic-independent
mechanisms; 3) identify the factors that can interact with TET proteins in sequential snapshots of lineage
specification. Upon completion of our work, we will elucidate the precise and multifaceted ...

## Key facts

- **NIH application ID:** 10212424
- **Project number:** 5R35GM138289-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ageliki Tsangaratou
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,288
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212424

## Citation

> US National Institutes of Health, RePORTER application 10212424, Epigenetic Regulation of Lineage Specification (5R35GM138289-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212424. Licensed CC0.

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