# Chromatin-based regulation of neural stem cells

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2021 · —

## Abstract

Neural stem cells (NSCs) hold promise for the treatment of a wide range of neurological disorders
common to Veterans such as traumatic brain injury (TBI) and Parkinson's disease. In addition to providing
cells for transplantation-based therapies, NSCs are also an important source of human neurons and glia for
drug discovery and development. To realize the full potential of NSCs for human therapy, it is important to
understand the molecular mechanisms that regulate the production of specific neural cell types. Our long-term
goal is to understand the cellular and molecular mechanisms by which NSCs produce specific types of neurons
and glia. The postnatal and adult mammalian brain harbors NSCs in the ventricular-subventricular zone (V-
SVZ). Importantly, V-SVZ NSCs retain distinct regional identities that underlie the production of different
neuronal subtypes. For instance, NSCs in the ventral V-SVZ produce neuron subtypes different from those
born from NSCs in the dorsal V-SVZ. Furthermore, such NSC regional identity is largely cell-intrinsic, and we
have shown that NSCs “remember” their regional identity through serial cell divisions. The expression of
Nkx2.1 defines a population of NSCs in the ventral V-SVZ. While sonic hedgehog (SHH) is required to induce
Nkx2.1 expression in ventral NSCs of the early embryonic brain, our Preliminary Studies indicate that SHH-
signaling is not required for the maintenance of Nkx2.1 expression in ventral V-SVZ NSCs, suggesting that
these cells epigenetically “remember” their regional identity. Mixed lineage leukemia-1 (Mll1) encodes a
chromatin regulator that is part of an evolutionarily conserved transcriptional memory system, and MLL1 is
required for normal V-SVZ neurogenesis. We found MLL1 protein enriched at Nkx2.1 regulatory elements, and
disruption of MLL1 activity with either conditional Mll1 deletion or an MLL1-specific chemical inhibitor resulted
in the loss of Nkx2.1 expression in ventral V-SVZ NSCs. After reversal of MLL1 inhibition, Nkx2.1 expression
remained low, but neuronal production was restored. Based on these findings, our central hypothesis is that
MLL1 is required to maintain NSC regional identity via specific chromatin state changes. In this renewal
application, we propose to investigate the role of MLL1 in NSC regional identity and determine the molecular
mechanisms by which MLL1 maintains region-specific gene expression. Given that NSC regional identity is a
critical aspect of their neurogenic potential, results obtained will have important implications for our ability to
produce specific types of neurons for human translational research and transplantation therapies. Furthermore,
these studies advance new basic, neurodevelopmental concepts regarding NSC regional identity, which may
be important to understanding how mutations in human MLL1 cause Weidemann-Steiner Syndrome, a
developmental disorder that includes intellectual disability and autism. Finally, discovering MLL1-dependent
mechani...

## Key facts

- **NIH application ID:** 10158398
- **Project number:** 5I01BX000252-11
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** DANIEL A LIM
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158398

## Citation

> US National Institutes of Health, RePORTER application 10158398, Chromatin-based regulation of neural stem cells (5I01BX000252-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10158398. Licensed CC0.

---

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