# Understanding the neurodevelopmental role and mechanism of histone demethylase JMJD3

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $379,525

## Abstract

JMJD3 (KDM6B) is a chromatin regulator with roles central to normal development as well as a wide range of
human diseases including cancer and human neurological disorders. For instance, mutations in JMJD3 are
autosomal recessive for familial intellectual disability, and de novo JMJD3 mutations are associated with
autism spectrum disorder (ASD). An important next step to understanding genetic causes of complex diseases
is to study disease-associated genes in mouse models. While it is known that JMJD3 is important to certain
aspects of neural cell development, whether JMJD3 deficiency can actually cause cognitive dysfunction has
not been known. Preliminary Studies indicate that JMJD3 is critical for the development of the mouse
hippocampal dentate gyrus (DG). In the DG, granule neurons are generated throughout life from a population
of neural stem cells (NSCs). Defective DG neurogenesis impairs many hippocampal-dependent behaviors and
has been associated with cognitive deficits including that of intellectual disability and ASD. Without Jmjd3,
NSCs failed to become established in the adult DG, and granule neuron production was severely decreased
and abnormal. In these mice, hippocampal-dependent learning was defective. Heterozygous deletion of
Jmjd3 also resulted in abnormal postnatal DG development, indicating that this process is sensitive to gene
dosage. Aim 1 is to determine the role of Jmjd3 in DG neurogenesis. In vivo experiments will test the
hypothesis that Jmjd3 regulates the postnatal expansion and establishment of the DG NSC population, and
that even reduced Jmjd3 gene dosage causes cognitive dysfunction. Single cell RNA sequencing analysis will
provide molecular insights into the observed phenotype and help guide mechanistic studies of Aim 2. Aim 2 is
to determine the mechanisms by which JMJD3 regulates gene expression. JMJD3 has demethylase activity for
histone 3 lysine 27 trimethylation (H3K27me3), which is a chromatin modification associated with
transcriptional repression. To investigate demethylase-dependent and potential demethylase-independent
activities of JMJD3, we have developed innovative CRISPR-based technologies to recruit JMJD3 proteins to
the genome. By developing a novel, easy-to-use method for mapping lamina-associated domains (LADs) – a
repressive nuclear compartment – we have also found that JMJD3 in NSCs is enriched at the genomic LAD
“borders,” which are genomic regions enriched for transcriptional regulatory elements. Thus, we propose
investigating the role of JMJD3 in regulating this aspect of higher-order chromatin structure. The proposed
neurodevelopmental and behavioral analyses combined with mechanistic studies is expected to provide a
scientific framework in which to begin understanding how human JMJD3 mutations can cause disease. The
studies of JMJD3 mechanism is also expected to be important to the broader field of chromatin-based
epigenetics as well as nuclear compartment-associated genome organization – a...

## Key facts

- **NIH application ID:** 10052136
- **Project number:** 1R01NS112357-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DANIEL A LIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,525
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052136

## Citation

> US National Institutes of Health, RePORTER application 10052136, Understanding the neurodevelopmental role and mechanism of histone demethylase JMJD3 (1R01NS112357-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10052136. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*