# Investigating the role of THAP transcription factor mediated regulation of cell proliferation in vertebrate development and neurodevelopmental disease

> **NIH NIH FI2** · U.S. NATIONAL INST/CHILD HLTH/HUMAN DEV · 2021 · —

## Abstract

Project Summary/Abstract
Despite the high prevalence rate (~2%) and socio-economic cost of intellectual disability (ID; IQ < 70), the
underlying genetic cause of most cases is unknown. The objective of this proposal is to investigate novel genetic
causes of ID. Many vertebrate THAP-domain containing transcription factors (TF) regulate neurodevelopment.
THAP11 mutation is associated with developmental delay and epilepsy, and mutations in THAP1 cause type 6
dystonias. THAP1/11 contribute to these disorders by regulating gene transcription by recruiting their cofactor,
host cell factor 1 (HCFC1), though the exact mechanism has been challenging to determine because complete
loss of either is embryonic lethal in mice. Mutations in another THAP gene, THAP7, segregate with ID, epilepsy,
and craniofacial defects in three families, suggesting THAP7 is a novel ID gene. The ability of THAP1/7/11
proteins to regulate cell proliferation may explain their role in neurodevelopment. Neural progenitors (NPCs) of
the developing cortex balance proliferation and differentiation to ensure cortical layers form properly; defects
lead to altered brain size and cognitive impairment. THAP1/11 regulate proliferation by tethering HCFC1, itself
implicated in ID, to cell cycle genes, leading to recruitment of chromatin modifiers. THAP7 loss does not arrest
cell growth, suggesting Thap7-/- mice may be viable. The long-term goal of this research is to investigate the role
of THAP TFs in normal neurodevelopment and ID using THAP7 as a model. How THAP7 regulates proliferation
remains unknown. While THAP7 likely acts as a TF and binds to the promoters of a few cell cycle genes, the
extent of THAP7’s function as a TF during neurodevelopment is untested. The proposed research will test the
following hypotheses 1) THAP7 promotes neurodevelopment by regulating cortical NPC proliferation, and
that mutation or loss of THAP7 leads to aberrant cortical development and 2) that THAP7 accomplishes
this by regulating expression of cell cycle genes via recruitment of HCFC1. Specific aims of this proposal
are as follows: investigate THAP’s ability to regulate proliferation of and act as a TF in neuroblastoma cells upon
loss, overexpression, or mutation of THAP7 using functional genomics (Aim 1) and to assess the function of
THAP7 in vivo (Aim 2) by generating Thap7 KO mice (CRISPR) and by modeling human ID via patient Thap7
knock-in (KI) mice. Mice will be assessed for neurodevelopmental defects, including cortical NPC composition.
The ability of THAP7 to act as a TF in NPCs will be determined via functional genomics analysis of Thap7 KO/KI
NPCs derived from in vitro differentiated mouse embryonic stem cells. The proposed research will reveal the
molecular and biological function of THAP7, and provide insight into how THAP proteins broadly contribute to
neurodevelopment and ID. The proposed research combined with the training plan, which includes provisions to
improve the PIs communication, gra...

## Key facts

- **NIH application ID:** 10273525
- **Project number:** 1FI2GM142571-01
- **Recipient organization:** U.S. NATIONAL INST/CHILD HLTH/HUMAN DEV
- **Principal Investigator:** Rachel Leigh Cosby
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273525

## Citation

> US National Institutes of Health, RePORTER application 10273525, Investigating the role of THAP transcription factor mediated regulation of cell proliferation in vertebrate development and neurodevelopmental disease (1FI2GM142571-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10273525. Licensed CC0.

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