# Repressive Heterochromatin Establishment by Polycomb Complexes

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

Project Summary
The goal of this proposal is to dissect the distinct molecular roles of Polycomb Repressive
Complexes 1 and 2 (PRC1&PRC2) and upstream factors in establishing silencing at
developmentally regulated genes. The PRCs are conserved chromatin modifiers that represses
transcription via chemical and structural alterations of chromatin architecture. PRC1 mutations
cause neurodevelopmental disorders characterized by microcephaly, intellectual disabilities,
and dysmorphic body features, while mutations in PRC2 are the main cause of Weaver
syndrome making it crucial to gain understanding about polycomb repression during early
development. Despite ubiquitous expression, PRC1 and PRC2 can target distinct sets of genes
for silencing in different cell lineages, resulting in cell-type specific expression. Though there are
decades of research on Polycomb protein function, a key unanswered question is how
polycomb repressive complexes select different target genes as cells differentiate into different
cell types. While we understand the interplay of PRC1 and PRC2 during the maintenance of
polycomb silencing, we do not understand the order of events in the establishment of new
polycomb domains at de novo silenced genes.
Others in the field have shown that correct PRC2 localization can be re-established de novo in
mouse embryonic stem cells (mESCs) after ablation, indicating that there is information
upstream of PRC2 dictating localization. Additionally, my preliminary data from a genome wide
knock out screen implicates several factors of interest in regulating polycomb establishment
including RNA binding protein ERH. I will investigate the regulatory role of PRC1 and these
additional factors identified by the screen in PRC2 localization during the establishment of
polycomb domains in mESCs with the following specific aims.
In Aim 1, I will utilize acute protein degradation to investigate PRC1’s ability to re-establish
correct localization on chromatin after depletion. Using a similar strategy with an orthogonal
dual-degron line, I will also determine if PRC1 is necessary for correct PRC2 localization during
establishment.
In Aim 2, I will investigate the functional roles of candidates I identified in my genome wide KO
screen during PRC2’s re-establishment on chromatin in mESCs, leveraging my lab’s expertise
in designing acute protein degradation lines. The experiments in this proposal will elucidate the
order of events and factors involved in the establishment of silent polycomb domains.
To achieve these aims, I have developed with my sponsor a rigorous and comprehensive
training program with three primary goals: 1) become an expert in epigenomics methods, 2)
sharpen my scientific communication skills to broad audiences, 3) increase proficiency in
bioinformatics and data analysis.
I am confident that my choice of sponsor combined with my diverse training background and
the collaborative nature of my training environment will enable me to achieve my ...

## Key facts

- **NIH application ID:** 10996853
- **Project number:** 1F31GM156018-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Segovia Garcia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996853

## Citation

> US National Institutes of Health, RePORTER application 10996853, Repressive Heterochromatin Establishment by Polycomb Complexes (1F31GM156018-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996853. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*