Mechanisms of lineage plasticity revealed by YY1 deficiency.

YY1 缺陷揭示的谱系可塑性机制。

基本信息

  • 批准号:
    10415006
  • 负责人:
  • 金额:
    $ 51.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Hematopoietic development is an ordered process in which stem cells give rise to multiple lineages. While early progenitors can be multipotent, lineage-specific progenitors reach a stage where they become exclusively committed to that lineage. For example, B and T cell lineages differentiate from lymphoid-primed progenitors produced in the bone marrow, and exclusive commitment to the B cell lineage occurs as cells transition from the pre-pro-B to the pro-B cell stage. Despite the commitment of pro-B cells to the B lineage, we have made the surprising discovery that conditional knock-out of the ubiquitous multi-functional transcription factor YY1 in pro-B cells, results in the loss of B lineage commitment and the consequent ability to develop into the T cell lineage both in vitro and in vivo. To understand the mechanistic basis for this surprising lineage plasticity, we have developed a new lineage tracing mouse line that will enable us to determine how YY1-null pro-B cells develop into T lineage cells (de-differentiation to more primitive progenitors, or trans-differentiation), assess the potential for YY1- null pro-B cells to develop into other hematopoietic lineages, and determine if YY1-null T cells also exhibit lineage plasticity (Aim 1). Mechanistically, lineage-specific transcription factors bind to DNA and regulate gene expression prior to subsequent large-scale alterations in chromatin structure needed for lineage commitment. Rigorous studies by our laboratory as well as others indicate that despite its ubiquitous expression pattern, YY1 controls long-range chromatin interactions (LRCIs) in a lineage- specific fashion. Our findings support the hypothesis that DNA binding by lineage-specific transcription factors enables YY1 recruitment to distinct genomic loci, thereby enabling YY1 to both generate LRCIs that stabilize lineage-appropriate gene expression, and to generate repressive chromatin marks (H3K27me3) at lineage-inappropriate genes. We will thus, compare the molecular genetic phenotype (gene expression patterns, chromatin accessibility, epigenetic structure, and chromatin folding) of YY1- null pro-B cells developed into DN1, DN2a, DN2b, DN3, DP, CD4+, and CD8+ T cells, compared to wild- type T lineage cells, as well as YY1 conditional knockout T lineage cells (Aim 2). We hypothesize that in the absence of YY1, T lineage development can proceed, but LRCIs needed to stably maintain lineage- specific gene expression, and heterochromatin needed for repression of alternative lineages will fail to fully develop, potentially enabling continuing lineage plasticity. Our experiments may reveal a common mechanism for controlling lineage plasticity, vastly expanding potential applicability of directing YY1-null cells into multiple lineages.
造血发育是一个有序的过程,其中干细胞产生多个谱系。

项目成果

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Michael Lee Atchison其他文献

Michael Lee Atchison的其他文献

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{{ truncateString('Michael Lee Atchison', 18)}}的其他基金

Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10555949
  • 财政年份:
    2023
  • 资助金额:
    $ 51.78万
  • 项目类别:
YY1-dependent chromatin structure stabilization of B lineage commitment
B 谱系定型的 YY1 依赖性染色质结构稳定
  • 批准号:
    10294039
  • 财政年份:
    2021
  • 资助金额:
    $ 51.78万
  • 项目类别:
YY1-dependent chromatin structure stabilization of B lineage commitment
B 谱系定型的 YY1 依赖性染色质结构稳定
  • 批准号:
    10652364
  • 财政年份:
    2021
  • 资助金额:
    $ 51.78万
  • 项目类别:
Mechanisms of lineage plasticity revealed by YY1 deficiency.
YY1 缺陷揭示的谱系可塑性机制。
  • 批准号:
    10620173
  • 财政年份:
    2021
  • 资助金额:
    $ 51.78万
  • 项目类别:
Mechanisms of lineage plasticity revealed by YY1 deficiency.
YY1 缺陷揭示的谱系可塑性机制。
  • 批准号:
    10275678
  • 财政年份:
    2021
  • 资助金额:
    $ 51.78万
  • 项目类别:
YY1-dependent chromatin structure stabilization of B lineage commitment
B 谱系定型的 YY1 依赖性染色质结构稳定
  • 批准号:
    10449263
  • 财政年份:
    2021
  • 资助金额:
    $ 51.78万
  • 项目类别:
The role of YY1 in constitutive and inducible DNA loop formation
YY1 在组成型和诱导型 DNA 环形成中的作用
  • 批准号:
    8911349
  • 财政年份:
    2014
  • 资助金额:
    $ 51.78万
  • 项目类别:
The role of YY1 in constitutive and inducible DNA loop formation
YY1 在组成型和诱导型 DNA 环形成中的作用
  • 批准号:
    9126585
  • 财政年份:
    2014
  • 资助金额:
    $ 51.78万
  • 项目类别:
The role of YY1 in constitutive and inducible DNA loop formation
YY1 在组成型和诱导型 DNA 环形成中的作用
  • 批准号:
    8749047
  • 财政年份:
    2014
  • 资助金额:
    $ 51.78万
  • 项目类别:
Developmental Control of Enhancer Function
增强子功能的发育控制
  • 批准号:
    8056649
  • 财政年份:
    2010
  • 资助金额:
    $ 51.78万
  • 项目类别:

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