# Spatiotemporal regulation of epigenetic silencing by macromolecular interactions

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $423,750

## Abstract

Summary
The development of the human body involves cell specification and cell fate transition starting from
the embryos. Precise coordination of gene expression networks is required: lineage-specific genes
are transcriptional activated during early development, while genes for ectopic lineages are repressed
in the process. The precise control of gene expression is governed by epigenetic chromatin
modifications. Recent advances showed that genes encoding epigenetic “writer” and “eraser”
enzymes are frequently mutated in human diseases. However, treatment or early prevention methods
are hampered by the lack of knowledge on how the epigenetic landscape is precisely regulated. We
are investigating how a critical histone methylation (trimethylation of lysine 27 on histone H3, or
H3K27me3) is precisely regulated. H3K27me3 is the hallmark for facultative heterochromatin, which
dynamically regulate gene repression during body development. During early differentiation,
H3K27me3 is deposited on pluripotency genes, erased on cardiac genes, and maintained on other
developmental genes for ectopic lineages. The dynamic level of H3K27me3 across the genome is
essential for the ON/OFF switch of gene expression, but it remained unclear how H3K27me3 is
regulated in a coordinated temporal and spatial manner. We hypothesize that key macromolecular
interactions including protein-protein and protein-nucleic acid interactions regulates the specificity of
the H3K27me3 “writer” enzyme – Polycomb Repressive Complex 2 or PRC2. Recent progress and
our preliminary data show that the dynamic interactions between PRC2 and its accessory proteins
play key roles in the spatiotemporal regulation of epigenetic silencing specificity. To test the
hypothesis, we propose to fully interrogate the mechanism by employing a series of separation-of-
function mutants. Understanding the mechanism will open to door to further identification of novel
therapeutical targets to manipulate gene expression through epigenetic mechanisms.

## Key facts

- **NIH application ID:** 10940821
- **Project number:** 1R35GM155228-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Yicheng Long
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,750
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940821

## Citation

> US National Institutes of Health, RePORTER application 10940821, Spatiotemporal regulation of epigenetic silencing by macromolecular interactions (1R35GM155228-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10940821. Licensed CC0.

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