# The role of class IIa Hdac in regulating cell fate choice in early cortical development.

> **NIH NIH P20** · UNIVERSITY OF NORTH DAKOTA · 2020 · $195,128

## Abstract

PROJECT SUMMARY/ABSTRACT. PROJECT 2, D. DARLAND.
Functional integration between neural stem cells (NSC) and vascular cells is critical for neural-glia formation
during cortical development and glioma progression. Vascular cells can act as epigenetic drivers to induce NSC
specification and tumor transformation. However, these epigenetic factors remain poorly defined. We will identify
epigenetic mechanisms that regulate NSC fate decisions in response to vascular investment. We have
established a unique NSC-vascular coculture system in which NSC adopt a glial fate in response to vascular
cues have used a transcriptome-level, unbiased screening approach that has identified Class IIa Hdacs as
potential candidates for the epigenetic drivers. Of the histone deacetylases (Hdacs) expressed, only the Class
IIa Hdacs expressed in the brain (Hdac 4, Hdac 5, Hdac 7) were upregulated in NSC in vascular coculture,
suggesting that they play a role in mediating NSC transition to glial cells. Based on results from the Cancer
Genome Atlas (TCGA), elevated levels of Class IIa Hdacs are also associated with human glioma tumor grades,
particularly Hdac 4 and Hdac 5. The Class IIa Hdacs have the unique ability to move from the cytoplasm to the
nucleus, recruiting protein partners such as Hdac3 and Mecp2 to facilitate deacetylation reactions. This property
makes them attractive candidates to transduce microenvironmental cues. We have developed a coculture
system that models NSC interactions with vascular cells (endothelial cells and pericytes) and will use this to
address the question of NSC fate decisions in response to vascular environmental cues in early cortical
development and in a glioma-vascular model. Here we test the hypothesis that changes in Class IIa Hdacs are
critical for gliogenesis in response to vascular cell developmental cues and in glioblastoma during cancer
progression. In Aim 1 we will test if Class IIa Hdacs are required for gliogenesis in a neural-vascular coculture
model. The working hypothesis is that increasing expression of Class IIa Hdacs expression precedes the cell
fate transition from NSC to glia under the influence of vascular cell-derived Lif derived. In Aim 2 we will test if
Class IIa Hdacs are required for glioma progression in a vascular coculture model. Since Class IIa Hdac are
upregulated in human glioblastoma, the working hypothesis is that Class IIa Hdacs are required for the
glioblastoma stage transition that occurs in a highly vascular microenvironment. We predict that the Class IIa
Hdacs regulate changes in chromatin structure by decreasing transcription of proliferation and stem-specific
genes and inducing gliogenesis during development or promoting glioma progression in response to vascular
investment. The proposed studies address a critical need to understand how microenvironment-induced,
acetylation-based modifications to chromatin influence cortical gliogenesis during development and in glioma
tumor progression. The model ...

## Key facts

- **NIH application ID:** 9976552
- **Project number:** 5P20GM104360-07
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** DIANE Catherine DARLAND
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,128
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976552

## Citation

> US National Institutes of Health, RePORTER application 9976552, The role of class IIa Hdac in regulating cell fate choice in early cortical development. (5P20GM104360-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976552. Licensed CC0.

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