# Defining Informative Loci to Enable Mechanistic Insight and Treatment of Chromatinopathies

> **NIH NIH R21** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $211,875

## Abstract

PROJECT SUMMARY
 Over recent several decades, genomic analyses have elucidated etiologies for hundreds of disorders
with syndromic and nonsyndromic intellectual disability (ID). However, this knowledge has not readily
translated into treatment for patients, partly due to therapy development strategies that focus solely on single
diseases. Many patients with ID have mutations in genes that encode chromatin-organizing proteins.
Mutations in cohesin, a key chromatin-regulating protein, cause overlapping clinical findings with patients who
have mutations in other chromatin regulatory complexes, including BAF/SWI-SNF and p160/NCOA.
 The long-term goal is to identify treatments to improve neurocognitive outcomes in children with
chromatin-regulatory disorders. The overall objective of this R21 is to identify common informative target
genes disrupted by chromatin regulatory gene mutations in experimentally approachable and patient-derived
cell models. The central hypothesis is that mutations in cohesin, BAF/SWI-SNF and p160/NCOA complexes
cause similar clinical features because they disrupt an overlapping set of target genes. The rationale is that
identification of common, reproducible chromatin disruptions will enable breakthrough work to rapidly screen
drugs in laboratory settings and enable confirmation of precision therapy in patient cells prior to treatment.
This central hypothesis will be tested by the following two specific aims: 1) Identify common regions of
chromatin disruption in HCT116 cells with heterozygous mutations in cohesin, BAF/SWI-SNF and p160/NCOA
complex genes; and 2) Identify common regions of chromatin disruption in patient-derived lymphoblastoid
cells. For the first aim, CRISPR-Cas9 will be used to create heterozygous loss-of-function mutations for each
of six chromatin-regulatory genes in a monogenic lab cell line. RNA-seq and ATAC-seq will be used to identify
resultant patterns of altered gene expression and chromatin accessibility. Under the second aim, the
investigators' large collection of heterogenous patient lymphoblastoid cell lines with mutations in three
chromatin-regulatory genes will be used to identify robust patterns of altered gene expression and chromatin
accessibility to enable assessment of future precision therapy.
 This work is innovative, in the applicant's opinion, because it focuses on a novel approach to
developing shared therapies for overlapping groups of rare ID disorders, and proposes a unique chromatin
accessibility assay for future small molecule screening. This work is significant because it is expected to
provide strong evidence to support widening the approach to additional chromatin disorders and pursing
compounds that correct these chromatin disruptions. Ultimately, such knowledge has the potential to offer new
opportunities for innovative treatments of intellectual disability.

## Key facts

- **NIH application ID:** 9958755
- **Project number:** 1R21HD101977-01
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** MATTHEW A DEARDORFF
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958755

## Citation

> US National Institutes of Health, RePORTER application 9958755, Defining Informative Loci to Enable Mechanistic Insight and Treatment of Chromatinopathies (1R21HD101977-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9958755. Licensed CC0.

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