# Epigenetic and transcriptional consequences of Intellectual Disability-associated mutations in the histone lysine demethylase KDM5.

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $46,036

## Abstract

ABSTRACT
Intellectual disabilities (ID) are a group of neurodevelopmental disorders characterized by difficulties in memory,
cognition, and adaptive function by the age of 18. Whole exome sequencing from patients with ID reveals
mutations in the genes encoding KDM5A, B, and C. One to three percent of X-linked ID (X-LID) is attributed to
the highly neuronally expressed paralog KDM5C. KDM5 proteins are best known for their enzymatic
demethylation of H3 that is tri-methylated on lysine 4 (H3K4me3), a chromatin modification associated with
transcriptionally active promoters. Though Kdm5c knockout mice show cognitive phenotypes, no clinically
relevant pathways have been identified and the mechanism by which KDM5 regulates transcription is still
unclear. Drosophila possess a single, well conserved ortholog of KDM5 in which we can model patient-
associated ID mutations to understand their effects on neuronal development. A previous study from our lab
modeling ID mutations in Drosophila reveals a reduction in expression of ribosomal protein genes (RPG), total
protein translation, and defects in both short and long-term memory. De novo translation is necessary for memory
formation and is found to be altered in several ID disorders. Importantly, restoring translational defects are an
emerging and potentially therapeutic means to improve the cognitive function of individuals with ID. Hindering
the development of any therapies is a lack of understanding of how KDM5 functions molecularly to regulate the
expression of RP and other genes, the extent to which this requires its canonical histone demethylase activity,
and how KDM5 function is altered by ID-associated mutations. Here, we specifically address these key issues
by systematically decoding the role of KDM5 in RPG expression by assessing promoter H3K4me3 levels, the
KDM5 interactome, and how these are altered by ID mutations.

## Key facts

- **NIH application ID:** 10460743
- **Project number:** 1F31GM146347-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Matanel Yheskel
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460743

## Citation

> US National Institutes of Health, RePORTER application 10460743, Epigenetic and transcriptional consequences of Intellectual Disability-associated mutations in the histone lysine demethylase KDM5. (1F31GM146347-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10460743. Licensed CC0.

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