A multi-enhancer hub at the<i>Ets1</i>locus controls T cell differentiation and allergic inflammation through 3D genome topology

Chandra, Aditi; Yoon, Sora; Michieletto, M.; Goldman, Naomi; Ferrari, Emily K.; Fasolino, Maria; Joannas, Leonel; Kee, Barbara L.; Henao‐Mejia, Jorge; Vahedi, Golnaz

doi:10.1101/2022.10.28.514213

Cited by 4 publications

(6 citation statements)

References 63 publications

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“…For the genomic region around the identified SNP, we noticed that Chandra et al. recently reported a multi-enhancer hub (in mouse genome) that can control T-cell differentiation and allergic inflammation through 3D genome topology [ 50 ]. By mapping the human peak region (chr11:128324060–128325230, hg38) containing the identified intergenic SNP (rs7933433, chr11:128324555, hg38) to the mouse genome, we find that the mapped peak region (chr9:32910554–32911593, mm10) is exactly located in the same region with the multi-enhancer hub reported by Chandra et al.…”

Section: Resultsmentioning

confidence: 99%

InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop

Zhang

Jiao

Wang

et al. 2023

Briefings in Bioinformatics

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Deciphering cell-type-specific 3D structures of chromatin is challenging. Here, we present InferLoop, a novel method for inferring the strength of chromatin interaction using single-cell chromatin accessibility data. The workflow of InferLoop is, first, to conduct signal enhancement by grouping nearby cells into bins, and then, for each bin, leverage accessibility signals for loop signals using a newly constructed metric that is similar to the perturbation of the Pearson correlation coefficient. In this study, we have described three application scenarios of InferLoop, including the inference of cell-type-specific loop signals, the prediction of gene expression levels and the interpretation of intergenic loci. The effectiveness and superiority of InferLoop over other methods in those three scenarios are rigorously validated by using the single-cell 3D genome structure data of human brain cortex and human blood, the single-cell multi-omics data of human blood and mouse brain cortex, and the intergenic loci in the GWAS Catalog database as well as the GTEx database, respectively. In addition, InferLoop can be applied to predict loop signals of individual spots using the spatial chromatin accessibility data of mouse embryo. InferLoop is available at https://github.com/jumphone/inferloop.

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Section: Resultsmentioning

confidence: 99%

InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop

Zhang

Jiao

Wang

et al. 2023

Briefings in Bioinformatics

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“…The provided functionalities for interrogating and ranking network communities at multiple levels will allow downstream analysis such as hyperconnected cliques (Petrovic et al, 2019) and multi-enhancer hubs (A. Chandra et al, 2022) that were previously studied in the context of oncogenes and immune cell development, respectively.…”

Section: Utility and Discussionmentioning

confidence: 99%

Loop Catalog: a comprehensive HiChIP database of human and mouse samples

Reyna,

Fetter,

Ignacio

et al. 2024

Preprint

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HiChIP enables cost-effective and high-resolution profiling of regulatory and structural loops. To leverage the increasing number of publicly available HiChIP datasets from diverse cell lines and primary cells, we developed the Loop Catalog (https://loopcatalog.lji.org), a web-based database featuring HiChIP loop calls for 1319 samples across 133 studies and 44 high-resolution Hi-C loop calls. We demonstrate its utility in interpreting fine-mapped GWAS variants (SNP-to-gene linking), in identifying enriched sequence motifs and motif pairs at loop anchors, and in network-level analysis of loops connecting regulatory elements (community detection). Our comprehensive catalog, spanning over 4M unique 5kb loops, along with the accompanying analysis modalities constitutes an important resource for studies in gene regulation and genome organization.

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“…However, these elements appear to be insufficient to prevent spreading of heterochromatin into the Ets1 locus in T cells thus resulting in variegated expression of the transgene. Recently a region located ~250 kb downstream of Ets1 was shown to function as a multi-enhancer for mouse Th1 cells (31).…”

Section: Multiple Putative Regulatory Elements Have the Potential To ...mentioning

confidence: 99%

“…TADs are further sub-divided into sub-TAD regions that contain one or a few genes along with regulatory elements such as gene enhancers or silencers that bind specific transcription factors (26)(27)(28). Recently, the organization TAD structures in the Ets1 locus in mouse and human T cells have been published (31). This analysis also identified a super-enhancer region located approximately 250 kb downstream of the Ets1 gene, which is required for CD4+ T helper 1 (Th1) differentiation (31).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the organization TAD structures in the Ets1 locus in mouse and human T cells have been published (31). This analysis also identified a super-enhancer region located approximately 250 kb downstream of the Ets1 gene, which is required for CD4+ T helper 1 (Th1) differentiation (31). In contrast to the situation in T cells, the genomic organization of the Ets1 locus and the regulatory elements and transcription factors that bind to them in B cells remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Sequences within and upstream of the mouse Ets1 gene drive high level expression in B cells, but are not sufficient for consistent expression in T cells

Kearly,

Saelee,

Bard

et al. 2024

Preprint

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The levels of transcription factor Ets1 are high in resting B and T cells, but are downregulated by signaling through antigen receptors and Toll-like receptors (TLRs). Loss of Ets1 in mice leads to excessive immune cell activation and development of an autoimmune syndrome and reduced Ets1 expression has been observed in human PBMCs in the context of autoimmune diseases. In B cells, Ets1 serves to prevent premature activation and differentiation to antibody-secreting cells. Given these important roles for Ets1 in the immune response, stringent control ofEts1gene expression levels is required for homeostasis. However, the genetic regulatory elements that control expression of theEts1gene remain relatively unknown. Here we identify a topologically-associating domain (TAD) in the chromatin of B cells that includes the mouseEts1gene locus and describe an interaction hub that extends over 100 kb upstream and into the gene body. Additionally, we compile epigenetic datasets to find several putative regulatory elements within the interaction hub by identifying regions of high DNA accessibility and enrichment of active enhancer histone marks. Using reporter constructs, we determine that DNA sequences within this interaction hub are sufficient to direct reporter gene expression in lymphoid tissues of transgenic mice. Further analysis indicates that the reporter construct drives faithful expression of the reporter gene in mouse B cells, but variegated expression in T cells, suggesting the existence of T cell regulatory elements outside this region. To investigate how the downregulation of Ets1 transcription is associated with alterations in the epigenetic landscape of stimulated B cells, we performed ATAC-seq in resting and BCR-stimulated primary B cells and identified four regions within and upstream of theEts1locus that undergo changes in chromatin accessibility that correlate toEts1gene expression. Interestingly, functional analysis of several putative Ets1 regulatory elements using luciferase constructs suggested a high level of functional redundancy. Taken together our studies reveal a complex network of regulatory elements and transcription factors that coordinate the B cell-specific expression ofEts1.

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A multi-enhancer hub at theEts1locus controls T cell differentiation and allergic inflammation through 3D genome topology

Cited by 4 publications

References 63 publications

InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop

InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop

Loop Catalog: a comprehensive HiChIP database of human and mouse samples

Sequences within and upstream of the mouse Ets1 gene drive high level expression in B cells, but are not sufficient for consistent expression in T cells

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