Dynamic regulation of FoxP3 expression controls the balance between CD4+ T cell activation and cell death. Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Figure 1 Multi-omic Mapping of Chromatin Architecture in Untreated and PMA-Treated THP-1 Cells (A) Hi-C contact matrix depicting normalized contact frequencies for untreated THP-1 cells (blue, top left) and PMA-treated THP-1 cells (red, bottom right). One loop is highlighted. (B) ATAC-seq, ChIP-seq, and RNA-seq signal tracks. (C and D) APA plots showing aggregated signal across all loops in both untreated (C) and PMA-treated (D) THP-1 cells. (E) Motif enrichment in loop anchors of untreated THP-1 cells. (F) Distribution of CTCF motif orientations at loop anchors. (G) RNA fragments per kilobase of transcript per million mapped reads (FPKM) values of genes binned by the number of loops that connect to their promoter. (H) RNA FPKM values of genes binned by the histone H3K27ac signal at the promoter-distal end of a loop. (I) H3K27ac signal binned by the histone H3K27ac signal at the other end of a loop. Significant differences (p. Figure 3 Expression and Function of Genes Correlate with Dynamic Loop Type and Distal Chromatin State (A) Schematic depictions of five loop classes. Red arrows indicate direction of change during PMA-induced differentiation of THP-1 cells. “Ac” refers to a change in H3K27ac as detected by ChIP-seq. (B) Counts per million versus log fold change for all transcripts measured by RNA-seq. Genes are colored according to the class of loop found at their promoter. (C) RNA FPKM values for each gene subset. (D and E) Selected GO terms enriched in genes sets at gained (D) and activated (E) loop anchors. Figure 4 Gained and Activated Loops Form Multi-loop Multi-enhancer Activation Hubs (A) The percentage of static or gained loops with H3K27ac peaks at the anchors. Asterisks indicate p. Figure 5 AP-1 Enriched at Enhancers Containing Loop Anchors in Both Gained and Activated Loops (A–E) Scatterplots depicting the percentage of lost (A), deactivated (B), static (C), activated (D), and gained (E) anchors that overlap TF footprints and the −log 10 p value of enrichment (Fisher’s exact test) for each TF. (F) Percentage of loop anchors that overlap an AP-1 footprint as a function of the loop subset and promoter or enhancer overlap. (G) RNA fold change of genes connected via a loop to distal TF footprints. FOS, JUN, and MAF points represent individual FOS-, JUN-, and MAF-related TF footprints. Log2 fold changes were median normalized to account for the fact that genes at loop anchors exhibited a shift toward upregulation during differentiation. (H) Twenty randomly chosen interaction communities containing a gained loop are shown. Loop anchors containing AP-1 footprints are indicated in green. See also Figure S5. The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi-loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription. Chromatin remodeling is the dynamic modification of architecture to allow access of condensed genomic DNA to the regulatory, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer.
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March 2018
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