# Investigating How Defects in The Maternal Germline Reprogramming of Histone Methylation Contribute to Inherited Disease

> **NIH NIH R56** · EMORY UNIVERSITY · 2022 · $387,122

## Abstract

Patterns of histone methylation can be propagated through cell division as a form of transcriptional memory to
maintain transcriptional states. At fertilization, this histone methylation must be reprogrammed to prevent the
inappropriate inheritance of transcriptional states in the progeny. My lab has shown in both C. elegans and
mice, that lack of reprogramming histone methylation at fertilization can lead to the epigenetic inheritance of
abnormal phenotypes. These phenotypes are reminiscent of defects observed in patients with mutations in the
H3K4me1/2 demethylase LSD1/KDM1A, and in Kabuki Syndrome, caused by mutations in other histone
modifying enzymes. This raises the possibility that maternal germ line reprogramming may be a susceptibility
point through which human mutations in histone modifying enzymes contribute to human disease. To
investigate this possibility my lab has generated a new hypomorphic allele of LSD1 in mouse oocytes. In this
proposal, we will use this new LSD1 mouse to address the following questions. Can hypomorphic maternal
LSD1 at fertilization lead to developmental delay and learning deficits observed in human LSD1 patients and
Kabuki Syndrome patients? How does maternal age and genetic background modulate phenotypes caused by
hypomorphic maternal LSD1? Does LSD1 cooperate in maternal reprogramming with the H3K9
methyltransferase SETDB1? What is the mechanism through which maternal loss of LSD1 contributes to
inherited defects? What are the genes/pathways that are affected by maternal loss of LSD1? How does
hypomorphic LSD1 at fertilization affect imprinted gene expression? Addressing these questions will begin to
determine whether defects in maternal epigenetic reprogramming can contribute to inherited human disease.

## Key facts

- **NIH application ID:** 10592730
- **Project number:** 1R56NS122964-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** David John Katz
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,122
- **Award type:** 1
- **Project period:** 2022-05-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592730

## Citation

> US National Institutes of Health, RePORTER application 10592730, Investigating How Defects in The Maternal Germline Reprogramming of Histone Methylation Contribute to Inherited Disease (1R56NS122964-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10592730. Licensed CC0.

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