# Mechanisms of de novo Germline Histone Mutations Underlying Developmental Disorders

> **NIH NIH K99** · ROCKEFELLER UNIVERSITY · 2022 · $135,562

## Abstract

Project Summary
Chromatin integrates environmental and intrinsic cellular cues to orchestrate nucleosome modifications,
therefore regulating basic cellular functions that are essential for cell fate and identity in normal development.
Mutations in enzymes that deposit or remove nucleosome modifications often dysregulate chromatin structure
and result in pathological gene expression programs in many human developmental disorders. As the basic unit
of the nucleosome, alterations in histone genes themselves have only been recently identified in children with
developmental disorders and their mechanistic and functional roles remain largely unknown. Given the
increasing number of histone germline mutations and lack of understanding of their impact, it is imperative to
establish animal models to elucidate their physiological functions and delineate underlying mechanisms. My goal
is to uncover the function of histone mutations during development by integrating biochemical and genomic
assays, along with employing animal models through the followings aims: (1) Investigate the mechanism of how
histone H4 mutants are recruited to heterochromatin, (2) Determine how histone H4 mutations regulate
chromatin accessibility and neural differentiation, and (3) Identify the function of histone mutations during
development. The central hypothesis guiding this proposal is that histone mutations alter heterochromatin
silencing, impact gene expression, and promote neural differentiation, which altogether contribute to brain
defects. This research will provide new insights into molecular mechanisms underlying histone germline
mutations and the epigenetic causes of developmental disorders. During the mentored period, I will gain training
in the following key skillsets: acquiring expertise in mouse models, expanding my knowledge of mouse brain
development and in vivo brain models of developmental disorders, deepening training in grant writing and
mentoring, as well as scientific career development. With acquisition of these valuable skills, the well-established
biochemical and genomics approaches in the Allis laboratory, the great training in neurogenesis and mammalian
brain development from my co-mentor Dr. Hatten, and strong support and expertise from my outstanding
collaborators, I will be in a unique position to apply diverse approaches to study histone germline mutations in
developmental disorders. Importantly, I will receive additional mentoring from my Scientific Advisory Committee,
along with fantastic mentorship from Dr. Allis and Dr. Hatten to facilitate my transition to independence. Together,
this training and support from the K99/R00 award will fulfill my career goal of becoming an independent
investigator in the field of chromatin and developmental biology.

## Key facts

- **NIH application ID:** 10525879
- **Project number:** 1K99HD107908-01A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Lijuan Feng
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $135,562
- **Award type:** 1
- **Project period:** 2022-08-25 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525879

## Citation

> US National Institutes of Health, RePORTER application 10525879, Mechanisms of de novo Germline Histone Mutations Underlying Developmental Disorders (1K99HD107908-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10525879. Licensed CC0.

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