Reprogramming Gene Regulatory Networks to a Hematopoietic Stem Cell State

将基因调控网络重编程为造血干细胞状态

基本信息

  • 批准号:
    10716641
  • 负责人:
  • 金额:
    $ 52.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Hematopoiesis is a continuous process of blood-cell production occurring through the orchestrated activity of hematopoietic stem cells (HSCs). Although HSCs have tremendous clinical utility due to their ability to reconstitute the hematopoietic system by transplantation, their benefit remains limited by the lack of matched donors. Direct reprogramming of endothelial cells into HSCs via induction of reprogramming factors has recently emerged as a promising alternative. The overall goal of our proposal is to reveal the molecular mechanisms by which the reprogramming factors FOSB, GFI1, RUNX1, and SPI1 (FGRS) revert endothelial cells to functional reprogrammed HSCs (reHSCs). Understanding the basis by which the genetic networks become rewired for this profound cell type conversion will provide insights into diverse forms of reprogramming, development, and disease. We discovered that early in the reprogramming process, FGRS directly coordinate two tasks: selection and activation of multipotent HSC enhancers and disruption of endothelial enhancers and transcription factors (TFs). We hypothesize that the effect of FGRS on endothelial TF binding is as crucial for reprogramming as the activation of multipotency enhancers, and we propose to dissect the underlying molecular mechanisms for these processes. Using single-cell multiomic (scRNA & ATAC-seq) profiling, we further discovered that in intermediate reprogramming, the relatively homogenous starting endothelial cells are replaced by heterogeneous HSC populations. How the transition from somatic (endothelial) to multipotent (HSC) regulatory programs occurs in individual cells undergoing in vitro reprogramming remains unknown. To potentiate in vivo reprogramming, we generated a novel transgenic mouse model that allows constant FGRS expression in all somatic tissues and facilitates the recording of all key bifurcating events that lead to HSC establishment and maintenance. Based on our studies, we propose to dissect the molecular and cellular mechanisms by which FGRS promote cell fate changes in the context of endothelial-to-HSC reprogramming. In our first aim, we will uncover the molecular mechanisms by which FGRS target and modulate endothelial and HSC gene regulatory networks. In the second aim, we will delineate the intrinsic and extrinsic signaling pathways that promote endothelial-to-HSC reprogramming. We expect that our program will yield fundamental insights into the control of mammalian cell identity and may lead to novel strategies to generate therapeutically relevant HSCs with high efficiency.
项目总结/文摘

项目成果

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Konstantinos Chronis其他文献

Konstantinos Chronis的其他文献

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{{ truncateString('Konstantinos Chronis', 18)}}的其他基金

Epigenetics and Transcriptomics Core
表观遗传学和转录组学核心
  • 批准号:
    10494613
  • 财政年份:
    2022
  • 资助金额:
    $ 52.19万
  • 项目类别:
Epigenetics and Transcriptomics Core
表观遗传学和转录组学核心
  • 批准号:
    10706503
  • 财政年份:
    2022
  • 资助金额:
    $ 52.19万
  • 项目类别:

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