# Understanding the role of Hdacs in zebrafish craniofacial development

> **NIH NIH R16** · UNIVERSITY OF SOUTH CAROLINA AT AIKEN · 2024 · $172,499

## Abstract

One third of all birth defects are associated with craniofacial malformation including lack of suture closure, cleft
palate, or failure of skeletal formation. Progress in understanding the origin of these diseases depends on
understanding the cellular and genetic mechanisms that produce normal craniofacial patterning. The zebrafish
is an excellent model system for studying the process of craniofacial development, as it is possible to observe
all stages of jaw formation, from development of cranial neural crest (CNC) cells, which migrate into the
pharyngeal arches and differentiate into skeletal cells, all the way through generation of bone and cartilage in a
few days. The ability to generate genetic mutations and transgenic lines in zebrafish allows for precise
dissection of molecular mechanisms involved in craniofacial patterning. Histone deacetylases (Hdacs) are
enzymes that function to regulate transcription during development. Human disorders and animal models
demonstrate that Hdacs are involved in the development of the CNC-derived skeleton. For example, Cornelia
de Lange syndrome, cleft palate disease, and Fetal Alcohol Syndromes all involve defects to CNC cells or
derivatives, and are associated with abnormal Hdac function. The long-term objective of this study is to reveal
how individual Hdacs interact with known and novel gene pathways to regulate specification, migration,
differentiation, and activity of CNC cells and their derivatives to pattern the craniofacial skeleton. The proposed
studies will focus on investigating the function of Hdac1 and protein complexes involving Hdac1 in zebrafish,
using data generated using RNA-Seq and ATAC-Seq and mutant lines with unknown craniofacial phenotypes
(i.e. phf21aa;ab, zmym2) to test the hypotheses that Hdac1 patterns post-migratory CNC cells through
regulation of patterning genes and growth of cartilage and bone. Using a chemical inhibitor screen, this study
will further elucidate the potential roles of other Hdacs (i.e. Hdac3, 6, 8) in development of the jaw skeleton in
the zebrafish model. Overall, the approach will include 1) investigation of genes and chromatin modifications
associated with patterning and skeletal development in hdac1 mutants 2) Analysis of the roles of factors in the
chromatin modifying Lsd1-CoREST-Hdac1 and Braf/Hdac complexes in skeletal development, 3) A reductive
strategy to test specific Hdac inhibitors applied to embryos (e.g. Romidepsin, TMP-195) in which the role of
particular classes or individual Hdacs on craniofacial development will be established, leading future reverse
genetics projects to generate novel Hdac mutants using CRISPR-Cas9. Research will involve undergraduates,
with a goal of exposing students to research design and to train them in critical thinking, molecular techniques,
data analysis, and communication skills.

## Key facts

- **NIH application ID:** 10937131
- **Project number:** 1R16GM154790-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT AIKEN
- **Principal Investigator:** April F DeLaurier
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $172,499
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937131

## Citation

> US National Institutes of Health, RePORTER application 10937131, Understanding the role of Hdacs in zebrafish craniofacial development (1R16GM154790-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10937131. Licensed CC0.

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