RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors

RUNX：CBFb 复合物限制成人淋巴细胞祖细胞产生胎儿限制的先天 T 细胞

• 批准号: 10195780
• 负责人: Joonsoo Kang
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195780
• 关键词: ATAC-seq; Address; Adopted; Adult; Architecture; Atopic Dermatitis; Biological Assay; Birth; Bone Marrow; Bone Marrow Cell Transplantation; Bone Marrow Cells; Cell Lineage; Cells; Chromatin; Complement Factor B; Complex; Core-Binding Factor; Data; Dermal; Development; Dose; Eczema; Embryo; Ensure; Epigenetic Process; Fetal Liver; Fetus; Gene Expression; Generations; Genes; Genetic Transcription; Genetic Variation; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterozygote; Homeostasis; Homing; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Institutes; Interleukin-17; Licensing; Life; Lung; Lymphocyte; Lymphoid; Lymphoid Cell; Lymphopoiesis; Malignant Neoplasms; Maps; Mediating; Modeling; Molecular; Mucous Membrane; Multipotent Stem Cells; Mus; Neonatal; Organ Culture Techniques; Patients; Phenocopy; Phenotype; Process; Property; Radiation Chimera; Regulator Genes; Reporting; Resolution; Sentinel; Skin; Specific qualifier value; T-Lymphocyte; Testing; Time; Tissues; To specify; Up-Regulation; Variant; Yolk Cell; Yolk Sac; base; cell type; cytokine; developmental plasticity; dosage; epigenome; fetal; fetus cell; fitness; genetic association; genome-wide; hematopoietic gene; hemogenic endothelium; human disease; in utero; in utero transplantation; in vivo; mouse model; neonate; overexpression; pathogen; pluripotency; progenitor; programs; reconstitution; stem; transcription factor; transcriptome; transcriptome sequencing

Summary During intrauterine development the immune system generates cell subsets that will colonize mucosal barriers. This process is restricted to a fetal/neonatal window as adult cells are unable to replenish mucosal lymphocytes. Despite this sharp temporal constraint, the molecular mechanisms underpinning adult versus fetal hematopoietic potential has not been fully elucidated. We propose that the expression of a specific set of fetal factors controlled by the dosage of the transcriptional complex RUNX:CBF2 is responsible for the acquisition of fetal developmental potential. We made the unexpected discovery that CBF2 haploinsufficiency confers adult hematopoietic stem cells the ability to reconstitute the prototypical type 3 cytokine producing T17 cells. Transcriptional analysis of adult hematopoietic progenitors in CBF2 heterozygous mice revealed the upregulation of genes usually active in embryos and likely controlled directly by RUNX:CBF2 complex. We propose that an ensemble of transcription factors (TFs) central to embryonic hematopoiesis can instruct adult progenitors to acquire fetal lymphopoietic potential. To test this hypothesis we will take advantage of the in utero transplantation assay that faithfully recapitulate the fetal niche. Developmental assays of conventional or genetically altered precursors in utero will help dissect the cellular and transcriptional requirements during the generation of mucosal innate-like lymphoid cells. We also propose to exploit the developmental plasticity imposed by CBF2 haploinsufficiency to rewire adult regulatory circuits in adult progenitors to adopt an embryonic developmental potential. Candidate fetal factors that are regulated by RUNX:CBF2 will be overexpressed in adult progenitors for their ability to generate immune subsets with a restricted fetal origin. In Aim 1, we will determine the overall chromatin landscape that characterizes CBF2 heterozygous adult progenitors and permit enhanced reconstitution of fetal-type innate lymphocytes. In Aim 2, we will identify the genes required for reprogramming adult hematopoietic progenitors towards fetal lymphopoietic potential. Our long term goal is to map with high granularity transcriptional changes that license hematopoietic progenitors to give rise to tissue resident fetal/neonatal-derived immune cells.

概括 在宫内发育期间，免疫系统产生的细胞子集将定植粘膜屏障。这个过程 由于成年细胞无法复制粘膜淋巴细胞，因此仅限于胎儿/新生儿窗口。尽管如此敏锐 临时约束，成年人与胎儿造血潜力支撑的分子机制尚未完全 阐明。我们建议通过转录剂量控制的一组特定胎儿因子的表达 复杂的Runx：CBF2负责获得胎儿发育潜力。我们使意外 发现CBF2单倍弥补的供认成人造血干细胞重建原型的能力 3型细胞因子产生T17细胞。 CBF2杂合的成年造血祖细胞的转录分析 小鼠揭示了通常活跃在胚胎中的基因的上调，并且可能直接由Runx：Cbf2复合物控制。 我们提出，胚胎造血的中心转录因子（TFS）的合奏可以指导成人祖细胞 获得胎儿淋巴细胞。为了检验该假设，我们将利用子宫内移植测定法 忠实地概括了胎儿利基市场。对子宫内常规或普遍改变的前体的发展评估 在粘膜先天样淋巴样细胞的产生过程中，将有助于剖析细胞和转录需求。 我们还建议探索CBF2单倍弥补以重新连接成人调节的发展可塑性 成人祖细胞中的圈子，以采用胚胎发育潜力。受到候选胎儿因素的调节 RUNX：CBF2将在成人祖细胞中过表达，因为它们具有受限胎儿的免疫亚群的能力 起源。在AIM 1中，我们将确定表征CBF2杂合成年的整体染色质景观 祖细胞并允许增强胎儿型先天淋巴细胞的重建。在AIM 2中，我们将确定基因 将成人造血祖细胞重编程为胎儿淋巴细胞的必需品所需。我们的长期目标是 用高粒度转录变化绘制，许可造血祖细胞引起组织居住 胎儿/新生儿衍生的免疫细胞。