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

研究 THAP 转录因子介导的细胞增殖调节在脊椎动物发育和神经发育疾病中的作用

• 批准号: 10273525
• 负责人: Rachel Leigh Cosby
• 金额: --
• 依托单位: U.S. NATIONAL INST/CHILD HLTH/HUMAN DEV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10273525
• 关键词: Investigating; role; THAP; transcription; factor

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, grantsmanship, and leadership skills and leverages the rich environment provided by NICHD, will ensure that the PI is fully prepared to transition into an independent position.

项目总结/文摘