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
- 来源:
- 关键词:B-LymphocytesBasophilsBindingBone MarrowCD8-Positive T-LymphocytesCell LineageCellsChromatinChromatin StructureCoupledDNADNA BindingDataDefectDevelopmentEpigenetic ProcessExhibitsGene ExpressionGene Expression ProfileGenesGenetic TranscriptionHematopoieticHematopoietic stem cellsHeterochromatinImmuneIn VitroLaboratoriesLewis lung carcinoma cellLymphoidMediatingMolecularMolecular GeneticsMolecular ProfilingMusNull LymphocytesPathway interactionsPatternPhenotypeProcessRegulationRepressionRoleSignal TransductionStructureSystemT-LymphocyteTherapeutic UsesTranscriptional RegulationYY1 Transcription Factoractivating transcription factorconditional knockoutdevelopmental plasticityeosinophilexperimental studygenomic locusin vivomacrophagemonocyteneutrophilnotch proteinprogenitorrecruitstem cellstranscription factortransdifferentiation
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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:
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