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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：
9340299
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9340299
关键词：
1p36 deletion syndrome Address Behavioral Brain Cell Differentiation process 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 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 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.

通过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。过程和细胞命运决定。它补充了遗传信息，并提供了额外的调节快速变化的细胞和有机体环境在发展过程中的反应机制。最近研究表明，组蛋白修饰酶的突变经常扭曲正常的发育“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稳态中起重要作用。重要的是，小鼠中Prdm 16缺失导致多种脑缺陷，包括小头畸形、大脑皮质破坏和胼胝体发育不全。然而，目前尚不清楚PRDM16如何调节神经祖细胞的功能以及其缺失如何导致正常神经发生的破坏。我们有最近发现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 PRDM16缺失导致神经干细胞中表观遗传修饰的失调，这在神经干细胞中起重要作用。定义了干细胞中的转录电路，这些电路定义了细胞的身份。