Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA378979 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5339700.fastq.gz | Fastqsanger.gz | |||
| SRR5339710.fastq.gz | Fastqsanger.gz | |||
| SRR5339720.fastq.gz | Fastqsanger.gz | |||
| SRR5339730.fastq.gz | Fastqsanger.gz | |||
| SRR5339740.fastq.gz | Fastqsanger.gz |
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Project description:Background: Unraveling the dynamic accessibility of regulatory chromatin at single-cell resolution is key to understanding stem/progenitor cell fate choices in health and disease. Nephron progenitor cells (NPCs) are a multipotent population giving rise to all cell types of the nephron, from the glomerular epithelium to the distal tubule. At any given time, the NPC’s choice to self-renew or differentiate and gain a new identity is determined not only by its transcription factor repertoire but also by the genome accessibility of the cognate cis-regulatory elements. Methods: We performed singleome and multiome analysis of chromatin accessibility and gene expression in thousands of embryonic and neonatal NPCs toward defining the regulatory landscape driving fate choices during nephrogenesis. Results: We show that chromatin accessibility recovers the diverse states of NPCs and precursor states of proximal and distal nephron epithelial cells. We define the key cell type-specific transcriptional regulators across pseudotime and NPC age. We find that chromatin accessibility in the podocyte lineage is established early in the trajectory and identify a subset of Forkhead factors exhibiting high chromatin activity in podocyte precursors. We also determined that strong linkages between cis-regulatory elements and expression levels distinguish fate-determining TFs. Conclusions: Single-cell mapping of accessible and active chromatin defines the regulatory landscape of nephrogenesis and provides a foundation for future studies in disease states characterized by abnormal nephrogenesis.
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Project description:Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. We performed dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis uncovers differential fate commitment dynamics between the two lineages as they exit the stem and progenitor stage. Collectively, these data provide novel insights into the global regulatory landscape during hematopoiesis.
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