# Regulation of DNA methylation by TETs and QSER1

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $664,338

## Abstract

The goal of this project is to discover fundamental epigenomic regulatory mechanisms that commit cells to
defined fates during early stages of embryogenesis. Early in development, commitment of the epiblast to germ
layers is followed by activation of key regulatory genes that drive lineage fate. These genes control normal
development and underlie the genetic basis for a broad range of human structural birth defects. We have studied
members of the TET family of hydroxylation enzymes, which regulate the demethylation of DNA, or block active
methylation of DNA, to control gene expression. We discovered requirements for TET enzymes during early
development in the zebrafish model, and for progenitor specification from human embryonic stem cells (hESCs).
Major gaps in understanding include: i) whether common or distinct mechanisms control demethylation for
progenitors from different germ layers, ii) whether different TET family members distinguish developmental
programs, and iii) how TETs are targeted to regulatory regions such as bivalent promoters. Suspecting that
additional proteins beyond TETs are needed to target DNA demethylation, we carried out a genome-wide
CRISPR screen and discovered QSER1, a previously uncharacterized chromatin-binding protein. We showed
that QSER1 is a key guardian of bivalent promoters and poised enhancers of developmental genes, especially
those residing in DNA methylation valleys, broadly across different cell fates. We found biochemical and genetic
interactions between QSER1 and TETs, suggesting that they cooperate to safeguard transcriptional and
developmental programs from methylation. QSER1 variant alleles were recently linked to coronary artery
disease, while haploinsufficiency of a QSER1 paralog, PRR12, is associated with multi-organ developmental
birth defect syndromes. We propose to fully explore the genetic relationships and downstream networks of
TET/QSER1 (TQ) family members, including how they function to control methylation and impact chromatin
structure in the context of two complementary model systems, zebrafish and hESCs. The zebrafish model allows
full genetic analysis of potentially compensatory or cooperating family members (including tet1, tet2, tet3, qser1,
and prr12), in an animal model with highly conserved developmental programs. The hESC model provides
outstanding biochemical and “omics” capacity, and validation in developing human progenitor and differentiated
cells. The multi-PI project represents a continued collaboration among investigators with complementary and
overlapping expertise, with a strong record of productivity. Specific Aims are proposed to determine the relative
contribution of these genes for directing early progenitor fate, discover the regulatory networks in which they
function, and to test interacting factors as candidates for linking TQ methylation control to chromatin modification.
Because regulation of methylation is a fundamental step of progenitor fate determination, our...

## Key facts

- **NIH application ID:** 10898762
- **Project number:** 5R01HD111256-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Todd R Evans
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $664,338
- **Award type:** 5
- **Project period:** 2022-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898762

## Citation

> US National Institutes of Health, RePORTER application 10898762, Regulation of DNA methylation by TETs and QSER1 (5R01HD111256-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898762. Licensed CC0.

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