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,其中干细胞产生多种谱系。
虽然早期祖细胞可以是多能的,但谱系特异性祖细胞达到了一个阶段,
完全忠于这个血统。例如,B和T细胞谱系从
在骨髓中产生的淋巴样引发的祖细胞,并且专门致力于B细胞
当细胞从前-原-B细胞阶段过渡到原-B细胞阶段时发生谱系。尽管承诺,
在将前B细胞敲除至B谱系的过程中,我们已经做出了令人惊讶的发现,
在前B细胞中普遍存在的多功能转录因子YY 1导致B谱系的丧失
在体外和体内,T细胞的定型和随后发育成T细胞谱系的能力。到
了解这种令人惊讶的谱系可塑性的机械基础,我们已经开发了一种新的谱系
追踪小鼠系,使我们能够确定YY 1缺失的pro-B细胞如何发育成T谱系细胞
(去分化为更原始的祖细胞,或转分化),评估YY1-
null pro-B细胞发育成其他造血谱系,并确定YY1-null T细胞是否也
表现出谱系可塑性(目标1)。从机制上讲,谱系特异性转录因子与DNA结合,
在随后的大规模染色质结构改变之前调节基因表达,
血统承诺我们实验室和其他实验室的严格研究表明,尽管
普遍存在的表达模式,YY1控制着谱系中的长距离染色质相互作用(LRCI),
具体的时尚。我们的研究结果支持了这样的假设,即DNA通过谱系特异性转录结合
因子使YY1能够募集到不同的基因组位点,从而使YY1能够产生LRCI
稳定适合谱系的基因表达,并产生抑制性染色质标记
(H3K27me3)在谱系不适当基因。因此,我们将比较分子遗传表型
(gene表达模式、染色质可及性、表观遗传结构和染色质折叠)。
与野生型相比,无效的pro-B细胞发育为DN1、DN2a、DN2b、DN3、DP、CD4+和CD8 + T细胞,
型T谱系细胞,以及YY 1条件性敲除T谱系细胞(Aim 2)。我们假设,
YY 1缺失时,T谱系发育可以进行,但LRCI需要稳定维持谱系-
特异性基因表达和抑制替代谱系所需的异染色质将无法
充分发展,潜在地使持续的谱系可塑性。我们的实验可能揭示了一个共同的
控制谱系可塑性的机制,极大地扩展了指导YY1-null的潜在适用性,
细胞分化成多个谱系。
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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