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PRDM16 function in neural development

PRDM16 在神经发育中的作用

基本信息

批准号：
9767868
负责人：
Yali Dou
金额：
$ 42.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767868
关键词：
1p36 deletion syndrome 3-Dimensional Address Behavioral Brain Cell Polarity Cell Proliferation Cell physiology Cells Cerebral cortex Chromatin Complement Corpus Callosum Cues Data Defect Development Developmental Process Disease Early Intervention Embryo Enhancers Environment Enzymes Epigenetic Process Exhibits Family Future Gene Expression Profile Genetic Genetic Transcription Genome Goals Histone H3 Histones Homeostasis Human In Vitro Infection Inflammation Intellectual functioning disability Kabuki Make-Up Syndrome Knockout Mice Lead Light Link Lysine Malignant Neoplasms Mediating Medicine Methylation Methyltransferase Microcephaly Mixed-Lineage Leukemia Modification Molecular Mus Mutation Neuroglia Neurons Neurophysiology - biologic function Nucleosomes Organoids Pathway interactions Phenotype Play Process Protein Family Protein Isoforms RNA Splicing Radial Recurrence Role Schizophrenia Science Seizures Stem cells Structure Surface Syndrome Therapeutic Intervention Ventricular Work adult stem cell autism spectrum disorder chromatin modification craniofacial development developmental disease epigenetic regulation genetic information genome-wide histone methylation histone methyltransferase histone modification human disease in vitro Model in vivo migration nerve stem cell neurodevelopment neurogenesis neuron development novel relating to nervous system response spatiotemporal stem cell biology stem cell differentiation transcriptome

项目摘要

Epigenetic regulation via covalent histone modifications plays an important role in dictating developmental processes and cell fate determination. It complements to genetic information and provides additional regulatory mechanisms in response to fast changing cellular and organismal environment during development. Recent studies show that mutations in histone modifying enzymes often skew the normal development ‘roadmap’ and consequently lead to human diseases. PRDM16 plays an important role in maintaining homeostasis of multiple adult stem cells including neural stem cells. Importantly, Prdm16 deletion in mice leads to multiple brain defects including microcephaly, disrupted cerebral cortex and agenesis of the corpus callosum. However, it remains unclear how PRDM16 regulate functions of neural progenitor cells and how its deletion leads to disruption of normal neurogenesis. We have recently found that PRDM16 is a histone methyltransferase that methylate histone H3. This finding links PRDM16 deletion to deregulation of epigenetic modifications in neural stem cells, which play essential roles in define transcription circuitries in stem cells that define cellular identity.

共价组蛋白修饰的表观遗传调控在决定发育中起着重要作用过程和细胞命运的决定。它补充了遗传信息，并提供了额外的监管在发育过程中对快速变化的细胞和组织环境做出反应的机制。近期研究表明，组蛋白修饰酶的突变通常会扭曲正常发育的“路线图”，从而导致人类疾病。PRDM16在维持包括神经干细胞在内的多种成体干细胞的动态平衡中起着重要作用。重要的是，小鼠Prdm16基因的缺失会导致多种脑缺陷，包括小头畸形、大脑皮层受损和胼胝体发育不全。然而，目前还不清楚PRDM16如何调节神经前体细胞的功能，以及它的缺失如何导致正常神经发生的中断。我们有新近发现，PRDM16是一种组蛋白甲基转移酶，可使组蛋白H3甲基化。这一发现链接到 PRDM16缺失导致神经干细胞表观遗传修饰的解除调控，这些修饰在定义干细胞中定义细胞身份的转录电路。