Chromatin 3D interactions mediate genetic effects on gene expression
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ABSTRACT:
PROVIDER: EGAS00001003485 | EGA |
REPOSITORIES: EGA
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Project description:Obtaining a complete picture of 3D-genome organization in tissues and disease states is often blocked by limiting amounts of tissue samples such that multiple types of genome-wide analyses cannot be performed on the same sample. Here, we found that starting with a pure population of memory CD4+ T-cells (mCD4-cells) we could get reproducible Hi-C data with just 50,000 cells. This population is only ~18.75% of the whole T-cell population, but presumably its uniformity enabled high reproducibility with low cell numbers so that Hi-C, RNA-Seq and potentially other analyses could be performed with repeats from the same donor. Moreover, there was strong correspondence between data from 3 different donors, suggesting that variability between individuals observed in other reports may reflect more the dynamic variability in the status of the immune system between individuals rather than variability in genome organization between individuals for a given cell type. We further observed uniform changes between samples and blood donors occurring during activation of the memory mCD4+ T cell population. While some genome organization changes occurred concomitant with changes in gene expression, there were at least as many changes that occurred without corresponding changes in expression. Counter to the hypothesis that TADs are largely invariant structures providing a scaffold for dynamic looping contacts between enhancers and promotors, we found that there were at least as many dynamic TAD changes as loops in this highly differentiated cell type. Stimulation with IL-2 alone triggered many changes in genome organization and many of these changes were strengthened by additional TCR and CD28 co-receptor stimulation. This suggests a stepwise process whereby mCD4+ T cells undergo sequential genome organization changes induced by distinct or combined stimuli likely to "prime" or “de-prime” them for expression responses to subsequent TCR-antigen ligation or additional cytokine stimulation
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Project description:Experimental methods for measuring 3D chromatin organization, such as Hi-C, are costly and have technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. We present C.Origami, a deep neural network model that performs de novoprediction of cell type–specific chromatin organization using as inputs the DNA sequence and two cell type–specific genomic features — chromatin accessibility and CTCF binding. C.Origami predicts chromatin organization within a 2 mega-base window and enables in silico experiments to examine the impact of genetic perturbations on chromatin interactions in pathologies such as cancer. We assess how individual DNA elements contribute to the organization of 3D chromatin organization and identify a compendium of cell type–specific trans-regulators across multiple cell types. We demonstrate that cell type–specific in silico genetic perturbation and screening, enabled by C.Origami, can be used to systematically discover chromatin regulatory mechanisms in both normal and disease-related biological systems.
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Project description:SATB1, a nuclear matrix-associated protein, has long been proposed to function as a global chromatin loop organizer in T cells. However, the precise roles of SATB1 in chromatin organization remain elusive. Here we show that the depletion of SATB1 in immortalized T cells led to pronounced changes in gene expression, particularly for genes involved in cell proliferation and T cell activation, as well as 3D genome architecture at multiple scales, including the A/B compartment, topologically associating domains (TADs), and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 led to increased association among the SATB1/CTCF co-occupied sites, as well as increased chromatin contacts across these sites, thereby altering the genome-wide chromatin loop landscape. SATB1 does not regulate genome architecture by modulating CTCF occupancy. Rather, the topological effects imposed by SATB1 may be attributed to SATB1-dependent anchoring of CTCF to the salt extraction-resistant nuclear matrix. Together, our findings suggest that the functional interplay between nuclear matrix and CTCF plays a critical role in orchestrating 3D genome organization.
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Project description:SATB1, a nuclear matrix-associated protein, has long been proposed to function as a global chromatin loop organizer in T cells. However, the precise roles of SATB1 in chromatin organization remain elusive. Here we show that the depletion of SATB1 in immortalized T cells led to pronounced changes in gene expression, particularly for genes involved in cell proliferation and T cell activation, as well as 3D genome architecture at multiple scales, including the A/B compartment, topologically associating domains (TADs), and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 led to increased association among the SATB1/CTCF co-occupied sites, as well as increased chromatin contacts across these sites, thereby altering the genome-wide chromatin loop landscape. SATB1 does not regulate genome architecture by modulating CTCF occupancy. Rather, the topological effects imposed by SATB1 may be attributed to SATB1-dependent anchoring of CTCF to the salt extraction-resistant nuclear matrix. Together, our findings suggest that the functional interplay between nuclear matrix and CTCF plays a critical role in orchestrating 3D genome organization.
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