# Liquid-Liquid Phase Separation in Heterochromatin Organization

> **NIH NIH R01** · LEHIGH UNIVERSITY · 2020 · $311,854

## Abstract

Project Summary
 The formation and dissolution of heterochromatin allows for different genes to be silenced
or upregulated, and can result in different cell types forming from the same genetic material.
Improper function of heterochromatin has been linked to the progression of many forms of cancer,
and recent work has also uncovered links to Amyotrophic Lateral Sclerosis (ALS) and
Frontotemporal Dementia (FTD). Heterochromatin function emerges in part from the ability of the
heterochromatic proteins (HP1) to recruits ligands and spread across the genome. In humans,
three members of the HP1 family have been identified, which can phase separate into liquid-like
proteinaceous droplets in vitro. The three proteins, while similar, display different responses to
phosphorylation, by either being more prone to phase separate or less. These HP1 proteins also
interact preferentially with methyl-binding proteins (MBDs), which are known to associate with
particular regions of the genome. The molecular details of heterochromatin-related proteins have
yet to be characterized due to the number of components, the disordered nature of many of the
components, and the wide range of relevant length scales over which the processes of seeding
and dissolution occur. This project will apply a combination of computational and theoretical
techniques, backed by experimental collaborations to provide a mechanistic understanding of the
driving forces underlying heterochromatin function and dysfunction by 1) identifying the interaction
modes relevant to HP1 and MBD phase separation at the atomic and molecular level 2)
quantifying the degree to which different proteins and ligands incorporate into multicomponent
assemblies/condensates 3) determining the extent to which post-translational modifications
perturb phase separation, and 4) characterize the incorporation of nucleic acids into protein-rich
condensates, determining the effects of DNA hybridization and RNA on incorporation and
dynamics within condensates. These approaches will generate detailed molecular-level
information on the assembly of many components into heterochromatin assemblies, and provide
the background knowledge needed for better understanding its regulation, and disease relevance.

## Key facts

- **NIH application ID:** 10122331
- **Project number:** 1R01GM136917-01A1
- **Recipient organization:** LEHIGH UNIVERSITY
- **Principal Investigator:** Jeetain Mittal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $311,854
- **Award type:** 1
- **Project period:** 2020-09-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122331

## Citation

> US National Institutes of Health, RePORTER application 10122331, Liquid-Liquid Phase Separation in Heterochromatin Organization (1R01GM136917-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10122331. Licensed CC0.

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