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.

总结 在子宫内发育过程中，免疫系统产生细胞亚群，这些细胞亚群将定植在粘膜屏障上。这个过程 局限于胎儿/新生儿期，因为成人细胞不能补充粘膜淋巴细胞。尽管这种尖锐 由于时间限制，支持成人与胎儿造血潜能的分子机制尚未完全阐明， 阐明。我们认为，一组特定的胎儿因子的表达受转录因子的剂量控制， 复合体RUNX：CBF β 2负责获得胎儿发育潜能。我们制造了意外 发现CBF β 2单倍不足赋予成人造血干细胞重建原型造血干细胞的能力。 产生3型细胞因子的T淋巴细胞17细胞。CBF β_2杂合子成人造血祖细胞的转录分析 小鼠揭示了通常在胚胎中有活性的基因的上调，并且可能直接由RUNX：CBF β 2复合物控制。 我们认为，胚胎造血的核心转录因子（TF）的集合可以指导成年祖细胞 获得胎儿淋巴细胞生成潜能为了验证这一假设，我们将利用子宫内移植试验 忠实地再现了胎儿的生态位。子宫内常规或遗传改变前体的发育试验 将有助于剖析粘膜先天样淋巴样细胞产生过程中的细胞和转录要求。 我们还建议利用CBF β 2单倍不足引起的发育可塑性来重新连接成年人的调节基因， 成年祖细胞中的电路，以采用胚胎发育潜力。受以下因素调控的候选胎儿因子： RUNX：CBF β 2将在成年祖细胞中过表达，因为它们具有产生具有限制性胎儿免疫的免疫亚群的能力。 起源在目标1中，我们将确定CBF β 2杂合子成人的整体染色质景观特征， 祖细胞，并允许增强的胎儿型先天淋巴细胞的重建。在目标2中，我们将识别 所需的重编程成人造血祖细胞向胎儿淋巴细胞生成的潜力。我们的长期目标是 以高粒度的转录变化作图，这些转录变化允许造血祖细胞产生组织驻留， 胎儿/胎儿来源的免疫细胞。