# Regulation of embryonic cell fate decision by histone methylation

> **NIH NIH F31** · EMORY UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY:
 Every year about 7.9 million infants are born with serious birth defects, including craniofacial,
intellectual disabilities, organs malformation and developmental delays. More importantly birth defects are the
leading cause of child mortality in United States. Recently, many children with birth defects were identified as
having mutations in histone modifying enzymes. These include Kabuki Syndrome patients and 3 children with
mutations in the histone demethylase LSD1/KDM1. These children all have neurodevelopmental disorders. It is
thought that the failure to properly regulate histone methylation in these patients leads to inappropriate
transcription. However, it is unclear to what extent inappropriate transcription is heritable within developing
embryos. It is also unclear how inappropriate transcription leads to defects. We have recently developed a C.
elegans model of inappropriately inherited histone methylation due to failure in epigenetic reprogramming at
fertilization. In C. elegans, two epigenetic enzymes, the H3K4me2 demethylase, SPR-5 (ortholog of LSD1),
and the H3K9 methyltransferase, MET-2 (ortholog of SetDB1), are maternally deposited into the oocyte. These
chromatin modifiers cooperate to reestablish the epigenetic ground state by modifying histone methylation.
Progeny of worms lacking SPR-5 and MET-2 accumulate high levels of H3K4me2, resulting in complete
sterility and developmental delay, caused by the improper maintenance of germline expression in the soma.
Importantly, the C. elegans embryonic lineage is completely invariant. As a result, spr-5;met-2 mutants provide
a unique opportunity to understand the rules governing how inappropriate histone methylation affects
transcription and cell fate at the single cell level. To do this, I will use confocal imaging to perform automated
lineage tracing. This will enable me to detect defects in the timing of cell division, the number of cell divisions,
and the survival/death of individual cells in every embryonic lineage. I will combine this with single cell RNA-
seq analysis to determine cell by cell, which somatic cells inappropriate express germline genes. By comparing
the lineage defects to the inappropriate expression of germline genes in every cell, I will learn the rules
governing how inappropriate histone methylation affects transcription and cell fate in developing tissues. Thus,
successful completion of this grant will provide a framework for understanding childhood diseases, such as
Kabuki Syndrome, caused by mutations in histone modifying enzymes.

## Key facts

- **NIH application ID:** 10251077
- **Project number:** 5F31HD100145-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Juan D Rodriguez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2019-09-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251077

## Citation

> US National Institutes of Health, RePORTER application 10251077, Regulation of embryonic cell fate decision by histone methylation (5F31HD100145-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10251077. Licensed CC0.

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