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. 2022 Jan 14;139(16):2483–2498. doi: 10.1182/blood.2021012077

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Copyright © 2022 American Society of Hematology.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Notch1 and Tcf1 regulate 3D organization of chromatin compartments and domains. (A) Induced CD45.2⁺ BM cells from Controls (black, n = 2), N1IC (red, n = 2), or N1IC Tcf7^Δ/Δ (blue, n = 2) mice were FACS purified for lineage^-, cKit⁺ (CD117), and Sca1⁺ BM progenitors (LSK) and processed for in situ Hi-C analysis. Characteristic flow cytometric plots are shown. (B) Juicebox-generated contact matrices from chromosome 15: whole chromosome, at 250 kb resolution (far left); 50 kb resolution (middle left); chromatin domains at 10 kb resolution (middle right); chromatin loops (blue squares) at highest resolution of 2.5 kb (far right) shown for Controls. The 1D regions corresponding to a contact matrix are indicated in the diagrams below and right. The intensity of each pixel represents the normalized number of contacts between a pair of loci. Maximum intensity: 1350, 293, 20, 3 (from left to right). (C-D) Chromatin subcompartment switching between (C) Controls vs N1IC and (D) N1IC Tcf7^Δ/Δ vs N1IC (left panels). X-axis indicates the number and direction of subcompartments switching: stable (0), toward active (+), and toward inactive (−). Association with gene expression differences (FDR < 0.1) for genes within dynamic compartments is shown in right panels. Unpaired Wilcoxon test, ****P value < .0001. (E) IGV CCCTC-Binding Factor (CTCF), chromatin accessibility, and H3K27ac profiles for all experimental groups shown for Tspan9. Tracks were group-scaled. Schematic representation of genetic loci is depicted below the profiles. Compartment tracks identified by Calder are shown at the bottom for all experimental conditions. (F) Quantitative comparison of identified TAD boundary changes differential, nondifferential, and shifted (nonoverlapping) in comparison N1IC vs Controls and N1IC vs N1IC Tcf7^Δ/Δ. (G) Proportion of TAD boundary changes classified into 5 categories for all comparisons as indicated. (H) Schematic depiction of Notch1- and Tcf1-dependent TAD regulating the expression of Grap2 gene. Hi-C matrix at 10 kb resolution is shown on top, TopDom and TADCompare analyzed TAD with differential boundary is shown below (highlighted in red) together with boundary score visualization. IGV profiles for CTCF and ATAC-seq are shown for N1IC LSKs. Tracks were group-scaled. Representation of genetic loci is depicted below the tracks.

Notch1 and Tcf1 regulate 3D organization of chromatin compartments and domains. (A) Induced CD45.2⁺ BM cells from Controls (black, n = 2), N1IC (red, n = 2), or N1IC Tcf7^Δ/Δ (blue, n = 2) mice were FACS purified for lineage^-, cKit⁺ (CD117), and Sca1⁺ BM progenitors (LSK) and processed for in situ Hi-C analysis. Characteristic flow cytometric plots are shown. (B) Juicebox-generated contact matrices from chromosome 15: whole chromosome, at 250 kb resolution (far left); 50 kb resolution (middle left); chromatin domains at 10 kb resolution (middle right); chromatin loops (blue squares) at highest resolution of 2.5 kb (far right) shown for Controls. The 1D regions corresponding to a contact matrix are indicated in the diagrams below and right. The intensity of each pixel represents the normalized number of contacts between a pair of loci. Maximum intensity: 1350, 293, 20, 3 (from left to right). (C-D) Chromatin subcompartment switching between (C) Controls vs N1IC and (D) N1IC Tcf7^Δ/Δ vs N1IC (left panels). X-axis indicates the number and direction of subcompartments switching: stable (0), toward active (+), and toward inactive (−). Association with gene expression differences (FDR < 0.1) for genes within dynamic compartments is shown in right panels. Unpaired Wilcoxon test, ****P value < .0001. (E) IGV CCCTC-Binding Factor (CTCF), chromatin accessibility, and H3K27ac profiles for all experimental groups shown for Tspan9. Tracks were group-scaled. Schematic representation of genetic loci is depicted below the profiles. Compartment tracks identified by Calder are shown at the bottom for all experimental conditions. (F) Quantitative comparison of identified TAD boundary changes differential, nondifferential, and shifted (nonoverlapping) in comparison N1IC vs Controls and N1IC vs N1IC Tcf7^Δ/Δ. (G) Proportion of TAD boundary changes classified into 5 categories for all comparisons as indicated. (H) Schematic depiction of Notch1- and Tcf1-dependent TAD regulating the expression of Grap2 gene. Hi-C matrix at 10 kb resolution is shown on top, TopDom and TADCompare analyzed TAD with differential boundary is shown below (highlighted in red) together with boundary score visualization. IGV profiles for CTCF and ATAC-seq are shown for N1IC LSKs. Tracks were group-scaled. Representation of genetic loci is depicted below the tracks.