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:
ORGANISM(S): Mus musculus
PROVIDER: GSE79875 | GEO | 2018/02/20
REPOSITORIES: GEO
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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.
2018-02-20 | GSE79874 | GEO
Project description:How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.
| S-EPMC5847274 | biostudies-literature
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.
2018-02-20 | GSE79422 | GEO
Project description:Integrative analysis of 3D nucleome and chromatin accessibility reveals a chromatin barrier established for T-lineage commitment during early T cell development
| PRJNA317301 | ENA
Project description:CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.
| S-EPMC5495066 | biostudies-literature
Project description:Pluripotent cells develop within the inner cell mass of blastocysts, a mosaic of cells surrounded by an extra-embryonic layer, the trophectoderm. We show that a set of somatic lineage regulators (including Hox, Gata and Sox factors) that carry bivalent chromatin enriched in H3K27me3 and H3K4me2 are selectively targeted by Suv39h1-mediated H3K9me3 and de novo DNA methylation in extra-embryonic versus embryonic (pluripotent) lineages, as assessed both in blastocyst-derived stem cells and in vivo. This stably repressed state is linked with a loss of gene priming for transcription through the exclusion of PRC1 (Ring1B) and RNA polymerase II complexes at bivalent, lineage-inappropriate genes upon trophoblast lineage commitment. Collectively, our results suggest a mutually exclusive role for Ring1B and Suv39h1 in regulating distinct chromatin states at key developmental genes and propose a novel mechanism by which lineage specification can be reinforced during early development.
| S-EPMC2927698 | biostudies-literature
Project description:CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3-D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely pre-existing in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3-D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of YY1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a pre-existing topological framework created by constitutive CTCF-mediated interactions.
2017-05-22 | GSE85185 | GEO
Project description:BACKGROUND:Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter-enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organization of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability. RESULTS:We have extended our [Formula: see text] framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We designed a novel machine learning approach that allows the prioritization of TFs binding to distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer-promoter loops involving YY1 in different cell lines. CONCLUSION:We present a novel approach that can be used to prioritize TFs involved in distal and promoter-proximal regulatory events by integrating chromatin accessibility, conformation, and gene expression data. We show that the integration of chromatin conformation data can improve gene expression prediction and aids model interpretability.
| S-EPMC7003490 | biostudies-literature
Project description:Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.
| S-EPMC3712340 | biostudies-literature
Project description:Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation is not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage specific genes. Surprisingly, the repressive chromatin profile of DFPs renders them unable to reform skin in allograft assays despite their multipotent potential. We hypothesized that chromatin de-repression was modulated by the H3K27me3 demethylase, Kdm6b/Jmjd3. Dermal fibroblast-specific deletion of Kdm6b/Jmjd3 in mice resulted in adipocyte compartment ablation and inhibition of mature dermal papilla functions, confirmed by additional single cell RNA-seq, ChIP-seq, and allografting assays. We conclude that DFPs are functionally de-repressed during murine skin development by Kdm6b/Jmjd3. Our studies therefore reveal a multimodal understanding of how DFPs differentiate into distinct fibroblast lineages, and provide a novel publicly-available multiomics search-tool.
| S-SCDT-10_15252-EMBJ_2023113880 | biostudies-other