Integrative analysis of 3D nucleome and chromatin accessibility reveals a chromatin barrier established for T-lineage commitment during early T cell development
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ABSTRACT:
PROVIDER: PRJNA317301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3269870.fastq.gz | Fastqsanger.gz | |||
| SRR3269880.fastq.gz | Fastqsanger.gz | |||
| SRR3269890_1.fastq.gz | Fastqsanger.gz | |||
| SRR3269890_2.fastq.gz | Fastqsanger.gz | |||
| SRR3269900_1.fastq.gz | Fastqsanger.gz |
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Project description:Hematopoiesis consists of step-wise commitment of multiple distinct intermediate differentiation stages before mature blood cells are generated1,2. Early progenitor cells have multiple cell fate potentials and retain plasticity to differentiate to alternative lineages, while later stages are fully committed to certain cell lineages and rarely alter their fates3,4. Although extensive studies have been performed on regulatory pathways in mature blood cells5-8, few have examined chromatin re-organization underlying the transcription programs in early progenitors of hematopoiesis. In particular, what roles chromatin organization plays in the cell fate commitment during the differentiation of early hematopoietic progenitor cells remains unclear. Here, we carried out an integrative analysis of 3D nucleome, chromatin accessibility and gene expression during early T cell development from hematopoietic stem cells (HSC) to CD4/CD8 double positive (DP) T cells. Analysis of these data sets revealed extensive A/B compartment flips and dynamic changes of chromatin accessibility at regulatory regions including promoters and enhancers during the development process. Remarkably, both the compartment flip and changes in chromatin accessibility display a monotonic pattern. While gradual and progressive changes in chromatin re-organization was observed at most development stages, an abrupt and striking genome-wide change in A/B compartment structure and chromatin accessibility occurred during the transition from double negative stage 2 (DN2) to DN3, which was accompanied with the loss of cell fate plasticity of DN3 to differentiate to alternative lineages, suggesting that a chromatin barrier is established at the DN3 stage to lock the cells in the T cell fate. The binding of PU.1, a key factor for the fate choice of early progenitor cells, and BCL11B, critically required for T cell commitment at late stages, was associated with increased long-distance interaction and chromatin accessibility and may coordinately contribute to the establishment of the 3D nucleome structure required for the lineage differentiation and commitment.
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Project description:Hematopoiesis consists of step-wise commitment of multiple distinct intermediate differentiation stages before mature blood cells are generated. Although extensive studies have been performed on regulatory pathways in mature blood cells, few have examined chromatin reorganization underlying the changes in transcription programs from early progenitors of hematopoiesis to mature immune cells. In particular, what roles chromatin organization plays in the cell fate commitment during the differentiation of early hematopoietic progenitor cells to committed T cells remains unclear. Here, we carried out an integrative analysis of 3D nucleome, chromatin accessibility and gene expression from hematopoietic stem cells (HSC) to CD4/CD8 double positive (DP) T cells. Analysis of these data sets revealed extensive reorganization of A/B compartments, topologically associating domains (TADs), and chromatin accessibility at transcriptional regulatory regions during the development process. Remarkably, all three levels of chromatin organization display a monotonic pattern of change. While gradual and progressive changes in chromatin reorganization was observed at most development stages, an abrupt genome-wide change in A/B compartment structure, TAD domain scores and chromatin accessibility occurred during the transition from double negative stage 2 (DN2) to DN3, which was accompanied with the loss of cell fate plasticity of DN3 to differentiate to alternative lineages, suggesting that a chromatin barrier is established at the DN3 stage to lock the cells in the T cell fate. This chromatin barrier may be reinforced by another genome-wide reorganization of chromatin at the DN4-to-DP transition. The binding of PU.1, a key factor for the fate choice of early progenitor cells, and BCL11B, critically required for T cell commitment at later stages, was associated with increased long-distance interaction and chromatin accessibility. Deletion of Bcl11b led to decreased chromatin interaction for BCL11B target genes, suggesting that it may contribute to the establishment of the 3D nucleome structure required for the lineage differentiation and commitment.
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Project description:Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells (SSCs) which constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here, we show that STAG3, this far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice. Due to its shorter chromatin residence, STAG3–cohesin attenuates topologically associating domains (TADs), rewires enhancer–promoter and Polycomb-mediated repressive interactions, and facilitates finer and more strengthened compartments, establishing a distinctive spermatogonial nucleome. Moreover, in the absence of STAG3–cohesin, SSCs show an impaired differentiation priming for spermatogenesis. Mitotic STAG3–cohesin is also expressed in human B cells and their malignant variations, promoting their propagation. Our findings on mitotic STAG3–cohesin elucidate a principle of male germline nucleome programming, demonstrate an unexpected mitotic role for STAG3 and might potentially improve understanding of human malignancies.
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