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Distal enhancers controlling motor neuron gene expression program

控制运动神经元基因表达程序的远端增强子

基本信息

批准号：
10307094
负责人：
Hynek Wichterle
金额：
$ 51.92万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307094
关键词：
Address Adopted Algorithms Amyotrophic Lateral Sclerosis Binding Binding Sites Biochemical Biological Assay Cell Fate Control Cells Chromatin Chromatin Loop Clinical Complex Computer Analysis Data Development Developmental Process Disease model Distal EP300 gene Elements Embryo Enhancers Event Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome engineering Genomics Goals Histone Acetylation Histones In Vitro Intercistronic Region Knock-out Learning Location Maps Mediator of activation protein Methods Modeling Molecular Motor Neuron Disease Motor Neurons Mus Mutate Nervous system structure Neurons Nucleic Acid Regulatory Sequences Pattern Process Promoter Regions Regulation Resolution Role Site Source Specificity Spinal System Testing Transcription Process Translating activating transcription factor base cell fate specification cell type cohesin computerized tools drug discovery embryonic stem cell homeodomain in vivo insight loss of function mammalian genome novel phenomenological models programs promoter recruit stem cell biology stem cell differentiation syntax transcription factor transcription regulatory network

项目摘要

Transcriptional programming of cell identity is gaining importance at both the basic developmental and the clinical levels. While the phenomenology of cell programming and reprogramming by forced expression of transcription factors is well described, the mechanisms of action of programming factors or the sequence of regulatory events resulting in a cell adopting a new identity are largely unknown. We are combining the strengths of stem cell biology with genomic and computational approaches to map the process of transcriptional programming of spinal motor neuron (MN) identity at a deep molecular level. We have developed efficient methods for the induction of MN identity in differentiating embryonic stem cells (ESCs) by the expression of programming transcription factors. Using this system, we combine biochemical, genomic, and computational analysis to address following questions: i) how is Isl1 recruited to transient enhancers in postmitotic motor neurons; ii) does Isl1 control enhancer activation; iii) are Klf factors bound to MN enhancers important for mediator and cohesin recruitment; iv) what motifs and factors coordinate interactions between distal and proximal MN-specific enhancers; v) can we infer the mechanisms controlling MN subtype specification and maturation by studying cell type and cell stage-specific regulatory regions in primary MNs. Together these studies will provide fundamental insight into the developmental processes underlying the specification of defined cell identity in the complex vertebrate nervous system and will provide a novel and efficient source of MNs for disease modeling, functional analysis, and drug discovery.

细胞身份的转录编程在基础发育和生物学中越来越重要。临床水平。虽然细胞编程和重编程的现象，通过强制表达的转录因子被很好地描述，编程因子的作用机制或转录因子的序列是已知的。导致细胞采用新身份的调节事件在很大程度上是未知的。我们正在结合干细胞生物学的优势与基因组和计算方法来映射的过程，脊髓运动神经元（MN）身份在深分子水平的转录编程。我们有开发了有效的方法，用于诱导分化胚胎干细胞（ESC）的MN身份，编程转录因子的表达。利用这个系统，我们联合收割机结合了生化，基因， i）Isl 1如何被募集到瞬时增强子中，有丝分裂后运动神经元; ii）Isl 1控制增强子激活; iii）是与MN增强子结合的Klf因子重要的调解和凝聚招募; iv）什么样的图案和因素协调之间的相互作用远端和近端MN特异性增强子; v）我们能否推断控制MN亚型的机制通过研究原代MN中的细胞类型和细胞阶段特异性调节区，来确定细胞的特异性和成熟。总之，这些研究将提供基本的洞察发展过程的基础，在复杂的脊椎动物神经系统中的确定的细胞身份的规范，并将提供一种新的， MN的有效来源，用于疾病建模，功能分析和药物发现。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Generative modeling of single-cell time series with PRESCIENT enables prediction of cell trajectories with interventions.

DOI：
10.1038/s41467-021-23518-w
发表时间：
2021-05-28
期刊：
Nature communications
影响因子：
16.6
作者：
Yeo GHT;Saksena SD;Gifford DK
通讯作者：
Gifford DK

Discovering differential genome sequence activity with interpretable and efficient deep learning.

DOI：
10.1371/journal.pcbi.1009282
发表时间：
2021-08
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Hammelman J;Gifford DK
通讯作者：
Gifford DK

Ranking reprogramming factors for cell differentiation.

DOI：
10.1038/s41592-022-01522-2
发表时间：
2022-07
期刊：
NATURE METHODS
影响因子：
48
作者：
Hammelman, Jennifer;Patel, Tulsi;Closser, Michael;Wichterle, Hynek;Gifford, David
通讯作者：
Gifford, David

Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression.