Key Takeaways & Executive Findings
- •• First comprehensive multi-omics dissection of chromatin structure dynamics during zebrafish HSPC development, including Hi-C, RNA-seq, ATAC-seq, and ChIP-seq. • Nascent HSPCs exhibit loose chromatin conformation with obscure hierarchical structures, which reorganize during maturation. • PU.1 is identified as a key transcription factor mediating promoter-involved chromatin loops and regulating HSPC gene expression. • Findings provide new insights into epigenetic regulation of vertebrate HSPC fate decision, with implications for improving in vitro HSPC generation.
Abstract
Background Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals. Understanding the mechanism underlying HSPC development is a holy grail of hematopoietic biology, which is helpful for HSPC clinical application. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision; however, its dynamic and role in HSPC development is poorly investigated. Methods We performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish for the first time, including Hi-C, RNA-seq, ATAC-seq, H3K4me3 and H3K27ac ChIP-seq. Results The chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure. We revealed the multi-scale reorganization of chromatin structure and its influence on transcriptional regulation and transition of cell fate during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression of HSPC. Conclusions Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factors involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.
1. Introduction
Understanding the regulatory mechanism underlying HSPC fate determination at different developmental stages is a primary goal of hematopoiesis biology. This is helpful in improving generation of functional HSPC in vitro. The HSPC development process is highly conserved between zebrafish and mammals and a series of important findings of HSPC ontology are based on zebrafish [1, 2]. For example, HSPC generation through endothelial-to-hematopoietic transition (EHT) is directly observed in zebrafish embryos [3]. There are three waves of hematopoiesis during zebrafish or mammalian development, with nascent HSPC arising from the ventral wall of dorsal aorta (DA) of zebrafish or aorta-gonad-mesonephros (AGM) region of mammals through the process of EHT, acquiring the ability of self-renewal and reconstruction of all blood lineages [4]. Then, this group of cells move to caudal hematopoietic tissue (CHT) of zebrafish or fetal liver of mammals to be fetal HSPC which can rapidly expand and differentiate [5, 6]. Finally, these cells seed into kidney marrow (KM) of zebrafish or bone marrow of mammals, to become adult HSPC and support adult hematopoiesis [7].
Although significant achievements have been made to know this process, a comprehensive understanding of the dynamic regulatory mechanisms governing HSPC development is still lacking. Recent studies showed that despite the critical role of transcription factors (TFs), epigenetic modifications are also important in HSPC fate decision [8, 9]. Chromatin conformation is fundamental for transcriptional regulation via multiple mechanisms, from long-distance interactions between enhancers and promoters to higher-order chromosome compartments and topologically associated domains (TADs) that can act as transcription restrained units [10, 11]. Recent studies have shown 3D genome rearrangement participat...
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Min He, Xiaoli Li, Bingxiang Xu, Yinbo Lu, Jingyi Lai, Yiming Ling, Huakai Liu, Ziyang An, Wenqing Zhang, Feifei Li (2026). Reprogramming of 3D genome structure underlying HSPC development in zebrafish. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03798-x
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Frequently Asked Questions
What is the main focus of this study?
The study investigates the dynamic reorganization of 3D chromatin structure during hematopoietic stem and progenitor cell (HSPC) development in zebrafish, using multi-omics approaches to understand transcriptional regulation and cell fate decisions.
What methods were used in this research?
The researchers performed Hi-C, RNA-seq, ATAC-seq, and ChIP-seq (H3K4me3 and H3K27ac) across different stages of HSPC development in zebrafish.
What are the key findings of the study?
The study revealed that nascent HSPCs have loose chromatin conformation with obscure structures, and identified PU.1 as a potential factor mediating promoter-involved loops and regulating gene expression during HSPC development.
Why is this research significant?
It provides a global view of chromatin structure dynamics during vertebrate HSPC development, offering new insights into epigenetic regulatory mechanisms that could improve in vitro generation of functional HSPCs for clinical applications.
How does this study relate to human hematopoiesis?
Since HSPC development is conserved between zebrafish and mammals, the findings may inform understanding of human hematopoiesis and aid in developing better strategies for HSPC expansion and transplantation.
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