Mechanisms of lineage plasticity revealed by YY1 deficiency.

YY1 缺陷揭示的谱系可塑性机制。

• 批准号: 10415006
• 负责人: Michael Lee Atchison
• 金额: $ 51.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10415006
• 关键词: B-Lymphocytes; Basophils; Binding; Bone Marrow; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Chromatin; Chromatin Structure; Coupled; DNA; DNA Binding; Data; Defect; Development; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Hematopoietic; Hematopoietic stem cells; Heterochromatin; Immune; In Vitro; Laboratories; Lewis lung carcinoma cell; Lymphoid; Mediating; Molecular; Molecular Genetics; Molecular Profiling; Mus; Null Lymphocytes; Pathway interactions; Pattern; Phenotype; Process; Regulation; Repression; Role; Signal Transduction; Structure; System; T-Lymphocyte; Therapeutic Uses; Transcriptional Regulation; YY1 Transcription Factor; activating transcription factor; conditional knockout; developmental plasticity; eosinophil; experimental study; genomic locus; in vivo; macrophage; monocyte; neutrophil; notch protein; progenitor; recruit; stem cells; transcription factor; transdifferentiation

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。