# Spatial Regulation of Epigenetic Memory

> **NIH NIH DP5** · YALE UNIVERSITY · 2024 · $418,750

## Abstract

Project Abstract: Faithful epigenetic maintenance of repression is essential to developmental processes and
is frequently disrupted in diseases like cancer. Repression is maintained, in part, by chromatin-associated
proteins, like HP1 and Polycomb (Pc) groups that biochemically alter chromatin by depositing histone marks
and spatially reorganize chromatin by compaction and/or phase separation mechanisms. As such, a physical
mechanism of repression through stable compaction or phase separation of chromatin has been proposed as
the function of heterochromatin organization, resulting in discrete open (active) and closed (repressed)
chromatin states. My prior studies challenge this dogma by revealing that while Pc-repressed regions are
compact and separated on average, at the single-locus level there exists a continuum of repressed chromatin
conformations. I propose that instead of providing a physical mechanism of transcriptional repression,
heterochromatin indirectly represses chromatin by regulating epigenetic memory. A mechanism of spatial
feedback, through which dynamic chromatin folding permits distal loci to reinforce the deposition and
maintenance of histone marks, serves as an epigenetic memory regulator without the need for a stably
compact or phase-separated organization. In this model, the rates of interaction frequencies, facilitated by cell
type- or locus-specific HP1/Polycomb proteins, refresh epigenetic marks in the face of nucleosome turnover
and cell division. This dynamic chromatin organization can regulate stability of epigenetic memory such that a
balance between maintenance of the existing epigenetic state and reprogrammability scales with cell plasticity.
In this proposal I will rigorously investigate this functional feedback between 3D genome organization and the
repressive epigenetic memory that underlies developmental gene regulation and cell plasticity. In Aim 1, I will
evaluate how dynamic chromatin organization regulates epigenetic memory during development through a
highly multiplexed epigenetic state and chromatin imaging methodology. This will enable me to
analyze single-locus epigenetic states and chromatin folding in an organoid model, unveiling how spatial
feedback shapes cellular reprogramming and fate commitment. In Aim 2, I will perform live imaging of
 heterochromatin dynamics which will allow me to define the motion of HP1 and Pc-bound chromatin and
measure how chromatin motion influences epigenetic memory. Finally, I will develop a super-resolution
imaging methodology to quantify protein-DNA interactions and chromatin folding to better understand the role
of Pc associated proteins’ ability to alter chromatin organization and create different levels of chromatin spatial
feedback.

## Key facts

- **NIH application ID:** 10923236
- **Project number:** 1DP5OD037361-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sedona Murphy
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2024-09-19 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923236

## Citation

> US National Institutes of Health, RePORTER application 10923236, Spatial Regulation of Epigenetic Memory (1DP5OD037361-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10923236. Licensed CC0.

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