Bcl11b in early T cell development

Bcl11b 在早期 T 细胞发育中的作用

基本信息

批准号：
8805822
负责人：
ELLEN V. ROTHENBERG
金额：
$ 40.5万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805822
关键词：
Accounting Affect Biological Cell Lineage Cell Maintenance Cell Maturation Cell Survival Cell division Cell physiology Cells Data Dendritic Cells Development E protein Event Exclusion Fetal Liver Gene Activation Gene Dosage Gene Rearrangement Gene Targeting Genes Growth Health Hematopoietic Hematopoietic System Imagery In Vitro Individual Knock-in Mouse Knock-out Laboratories Link Maintenance Mediating Modeling Molecular Multipotent Stem Cells Myelogenous Natural Killer Cells One-Step dentin bonding system Pathway interactions Pattern Phenotype Play Process Proteins Publishing Reporter Reporter Genes Repression Role Science Signal Transduction Specificity Staging Stem cells System T-Cell Development T-Cell Receptor Genes T-Lymphocyte TCF3 gene Testing Time Work base cell type daughter cell developmental plasticity macrophage mast cell notch protein operating under the influence progenitor programs self-renewal stem tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): T cell lineage commitment is known to depend on a combination of transcription factors operating under the influence of Notch-Delta signaling. However, the exact roles of these factors in the molecular mechanism of lineage commitment have remained elusive. One problem is that all of the established factors themselves have roles in stem-cell maintenance and/or in other hematopoietic cell types as well as in T cells, even though the precise combination used for T-cell specification may be unique. Another problem is the complexity of the choices that are excluded during lineage commitment. T-cell precursors appear to retain access to the very distinct pathways of natural killer (NK) cell development and dendritic- cell development, possibly also to mast-cell and macrophage development, until a midpoint in their specification, and then appear to lose all these alternative potentials at once. At the same time, the cells appear to alter their self-renewal potential. It has been difficult to account for all these changes in a one- step process, especially in the absence of any known regulatory function that is clearly T-cell specific. What has been missing is a T-lineage specific regulatory factor that can be shown to control a precisely defined subset of these events. This is the role that we propose is played by Bcl11b, a recently characterized transcription factor with a highly T-lineage specific pattern of expression within the hematopoietic system. Bcl11b induction immediately precedes T-lineage commitment, and our preliminary data with a conditional Bcl11b knockout imply that this factor controls a discrete subset of lineage commitment functions, involving the repression of NK fates and stem or progenitor cell-specific maintenance pathways. In this application, we propose to test this model and to use Bcl11b to clarify regulatory linkages in the commitment process. The aims are: 1. To use Bcl11b deficiency to dissect component processes within the T-lineage commitment mechanism: (a) exclusion of NK and stem-cell regulatory programs as related to exclusion of myeloid, B, and other hematopoietic programs; and (b) commitment mechanisms that may distinguish 12 from 34 lineage T cells 2. To determine the regulatory links between Bcl11b and the Id/E protein ratio in early T-cell development 3. To determine the direct targets of Bcl11b and the ordered pathway through which Bcl11b action promotes T-lineage identity 4. To track T-lineage specification and commitment at the single cell level using new fluorescent knock- in reporters incorporated in the Bcl11b locus.

描述（由申请人提供）：已知T细胞谱系承诺取决于在Notch-Delta信号传导影响下运行的转录因子的组合。但是，这些因素在谱系承诺的分子机制中的确切作用仍然难以捉摸。一个问题是，即使用于T细胞规范的精确组合可能是唯一的，所有已建立的因素本身在干细胞维持和/或其他造血细胞类型以及T细胞中都具有作用。另一个问题是谱系承诺中排除的选择的复杂性。 T细胞前体似乎保留了对天然杀手（NK）细胞发育和树突状细胞发育的非常独特的途径的访问权限，可能还可以用于桅杆和巨噬细胞的发展，直到其规格中的中点，然后似乎丢失了所有这些替代潜力立刻。同时，细胞似乎改变了其自我更新潜力。很难在一个步骤过程中考虑所有这些变化，尤其是在没有明显特定于T细胞的任何已知调节函数的情况下。缺少的是一个特定的调节因子，可以证明可以控制这些事件的精确定义子集。这是我们提出的作用BCL11b，BCL11b是最近表征的转录因子，具有高度T-Linege在造血系统中的表达模式。 BCl11b诱导直接在T-linege承诺之前，我们的初步数据具有条件Bcl11b敲除，这意味着该因素控制着谱系承诺函数的离散子集，涉及NK命运和STEM或祖细胞细胞特异性维持途径的抑制。在此应用程序中，我们建议测试此模型并使用BCL11B来澄清承诺过程中的监管联系。目的是：1。使用BCL11B缺乏识别T-linege承诺机制内的组件过程：（a）排除与排除髓样，B和其他造血程序有关的NK和Stem-Cell调节程序；（b）可能将12与34个谱系T细胞区分开的承诺机制2。确定早期T细胞发育中Bcl11b与ID/E蛋白比之间的调节联系3。确定BCL11B的直接靶标和有序的途径Bcl11b动作通过此促进T-linege身份4。使用BCL11b基因座中纳入的记者中的新荧光敲击器跟踪单细胞水平的T-linege规范和承诺。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment.

DOI：
10.7554/elife.37851
发表时间：
2018-11-20
期刊：
eLife
影响因子：
7.7
作者：
Ng KK;Yui MA;Mehta A;Siu S;Irwin B;Pease S;Hirose S;Elowitz MB;Rothenberg EV;Kueh HY
通讯作者：
Kueh HY

Transcriptional drivers of the T-cell lineage program.

DOI：
10.1016/j.coi.2011.12.012
发表时间：
2012-04
期刊：
Current opinion in immunology
影响因子：
7
作者：
Rothenberg EV
通讯作者：
Rothenberg EV

Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells.

DOI：
10.1016/j.immuni.2018.01.013
发表时间：
2018-02-20
期刊：
Immunity
影响因子：
32.4
作者：
Hu G;Cui K;Fang D;Hirose S;Wang X;Wangsa D;Jin W;Ried T;Liu P;Zhu J;Rothenberg EV;Zhao K
通讯作者：
Zhao K

Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control.

DOI：
10.1016/bs.ai.2015.09.002
发表时间：
2016
期刊：
Advances in immunology
影响因子：
0
作者：
Rothenberg EV;Ungerbäck J;Champhekar A
通讯作者：
Champhekar A

Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16.

DOI：
10.1038/s41590-018-0238-4
发表时间：
2018-12
期刊：
Nature immunology
影响因子：
30.5
作者：
Hosokawa H;Romero-Wolf M;Yui MA;Ungerbäck J;Quiloan MLG;Matsumoto M;Nakayama KI;Tanaka T;Rothenberg EV
通讯作者：
Rothenberg EV