RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors
RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors
批准号:
10195780
负责人:
Joonsoo Kang
金额:
$25.13万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-13 至 2022-12-31
关键词:
ATAC-seqAddressAdoptedAdultArchitectureAtopic DermatitisBiological AssayBirthBone MarrowBone Marrow Cell TransplantationBone Marrow CellsCell LineageCellsChromatinComplement Factor BComplexCore-Binding FactorDataDermalDevelopmentDoseEczemaEmbryoEnsureEpigenetic ProcessFetal LiverFetusGene ExpressionGenerationsGenesGenetic TranscriptionGenetic VariationGoalsHealthHematopoiesisHematopoieticHematopoietic stem cellsHeterozygoteHomeostasisHomingHumanImmuneImmune System DiseasesImmune responseImmune systemImmunityInstitutesInterleukin-17LicensingLifeLungLymphocyteLymphoidLymphoid CellLymphopoiesisMalignant NeoplasmsMapsMediatingModelingMolecularMucous MembraneMultipotent Stem CellsMusNeonatalOrgan Culture TechniquesPatientsPhenocopyPhenotypeProcessPropertyRadiation ChimeraRegulator GenesReportingResolutionSentinelSkinSpecific qualifier valueT-LymphocyteTestingTimeTissuesTo specifyUp-RegulationVariantYolk CellYolk Sacbasecell typecytokinedevelopmental plasticitydosageepigenomefetalfetus cellfitnessgenetic associationgenome-widehematopoietic genehemogenic endotheliumhuman diseasein uteroin utero transplantationin vivomouse modelneonateoverexpressionpathogenpluripotencyprogenitorprogramsreconstitutionstemtranscription factortranscriptometranscriptome sequencing
中文摘要
摘要
在宫内发育期间,免疫系统产生的细胞亚群将定植于粘膜屏障。这一过程
仅限于胎儿/新生儿窗口,因为成年细胞无法补充粘膜淋巴细胞。尽管如此,
时间限制,支持成人和胎儿造血潜力的分子机制尚未完全阐明
已澄清。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
复杂的RUNX:CBF2负责获得胎儿的发育潜力。我们制造了意想不到的东西
发现CBF2单倍体功能不全使成人造血干细胞具有重建原型的能力
产生T17细胞的3型细胞因子。CbF-2杂合子成人造血祖细胞的转录分析
小鼠发现,通常在胚胎中活跃的基因上调,可能直接受到RUNX:CbF2复合体的控制。
我们认为,胚胎造血中心的转录因子(TF)的集合可以指导成年祖细胞
以获得胎儿的淋巴生成潜能。为了验证这一假设,我们将利用子宫内移植试验。
忠实地概括了胎儿的利基环境。常规或转基因前体细胞在子宫内的发育分析
将有助于剖析黏膜先天淋巴样细胞生成过程中的细胞和转录需求。
我们还建议利用cbf2单倍体不足带来的发育可塑性来重新连接成人调节。
在成年祖细胞中采用胚胎发育潜力的回路。候选胎儿因子受以下因素调节
RUNX:Cbf2将在成年祖细胞中过表达,因为他们有能力与受限的胎儿产生免疫亚群
起源。在目标1中,我们将确定cbf2杂合子成体的整体染色质景观。
并允许增强胎儿型先天淋巴细胞的重建。在目标2中,我们将识别基因
将成人造血祖细胞重新编程为胎儿淋巴生成潜能所需。我们的长期目标是
绘制允许造血祖细胞产生组织驻留的高粒度转录变化图
胎儿/新生儿来源的免疫细胞。
英文摘要
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:CBF2 is responsible for the acquisition of fetal developmental potential. We made the unexpected
discovery that CBF2 haploinsufficiency confers adult hematopoietic stem cells the ability to reconstitute the prototypical
type 3 cytokine producing T17 cells. Transcriptional analysis of adult hematopoietic progenitors in CBF2 heterozygous
mice revealed the upregulation of genes usually active in embryos and likely controlled directly by RUNX:CBF2 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 CBF2 haploinsufficiency to rewire adult regulatory
circuits in adult progenitors to adopt an embryonic developmental potential. Candidate fetal factors that are regulated by
RUNX:CBF2 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 CBF2 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.
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会议论文
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Production of animal models to define how CTLA-4 impacts to T1D susceptibility
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海外基金