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

基本信息

批准号：
10328570
负责人：
Joonsoo Kang
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2021-01-13 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328570
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

项目摘要

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.

概括在子宫内发育过程中，免疫系统会产生细胞亚群，这些细胞亚群将在粘膜屏障上定殖。尽管这种情况很明显，但由于成人细胞无法补充粘膜淋巴细胞，因此仅限于胎儿/新生儿窗口。由于时间限制，支撑成人与胎儿造血潜力的分子机制尚未完全阐明我们提出，一组特定的胎儿因子的表达受转录剂量的控制。复杂的RUNX：CBF2负责胎儿发育潜力的获得我们做出了意想不到的事情。发现 CBF2 单倍体不足赋予成体造血干细胞重建原型的能力 CBF2 杂合子中产生 3 型细胞因子的 T17 细胞的转录分析。小鼠揭示了通常在胚胎中活跃的基因的上调，并且可能由 RUNX:CBF2 复合物直接控制。我们提出，胚胎造血中心的转录因子（TF）集合可以指导成年祖细胞为了获得胎儿淋巴细胞生成潜力，我们将利用宫内移植试验来检验这一假设。忠实地再现了子宫内传统或基因改变前体的发育测定。将有助于剖析粘膜先天样淋巴细胞生成过程中的细胞和转录要求。我们还建议利用 CBF2 单倍体不足所施加的发育可塑性来重新连接成人监管成年祖细胞中采用受胚胎发育潜力调节的候选胎儿因子的回路。 RUNX：CBF2 将在成年祖细胞中过度表达，因为它们能够生成具有受限胎儿的免疫子集在目标 1 中，我们将确定表征 CBF2 杂合成人的整体染色质景观。祖细胞并允许增强胎儿型先天淋巴细胞的重建。在目标 2 中，我们将鉴定这些基因。将成人造血祖细胞重新编程为胎儿淋巴细胞生成潜力所需的。我们的长期目标是。以高粒度转录变化进行映射，使造血祖细胞产生组织驻留胎儿/新生儿衍生的免疫细胞。