Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation

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

doi:10.1016/j.immuni.2023.05.004

Cited by 9 publications

(6 citation statements)

References 80 publications

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“…The super-enhancer described above that is located downstream of the Ets1 gene is needed for differentiation of Th1 cells (Chandra et al, 2023). As expected based on its role in Th1 cells, CD4 + CD45RB high T cells from mice lacking this super-enhancer sequence (Ets1-SEÀ/À mice) cannot induce colitis when transferred to Rag1 knockout mice (Chandra et al, 2023). Together, these various studies provide substantial evidence that corroborates an important role for Ets1 in IBD.…”

Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 64%

“…Functional blocking of gp130 by an inhibitor called SC144 led to reduced AD symptoms (Lee et al, 2019). Recently, a super-enhancer region located approximately 250 kb downstream of the mouse Ets1 gene has been identified (Chandra et al, 2023). A homologous region of the human genome contains numerous SNPs associated with allergy, asthma, and AD (Hinds et al, 2013;Paternoster et al, 2015), suggesting that these SNPs may affect expression of Ets1 in T cells of patients with AD and related conditions.…”

Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 99%

“…The cold-inducible RNA-binding protein (CIRBP) was identified as a gene regulated by Ets1 which is involved in Th1 cell-driven immune responses in IBD (He et al, 2022). The super-enhancer described above that is located downstream of the Ets1 gene is needed for differentiation of Th1 cells (Chandra et al, 2023). As expected based on its role in Th1 cells, CD4 + CD45RB high T cells from mice lacking this super-enhancer sequence (Ets1-SEÀ/À mice) cannot induce colitis when transferred to Rag1 knockout mice (Chandra et al, 2023).…”

Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 99%

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An update on the roles of transcription factor Ets1 in autoimmune diseases

Garrett‐Sinha

2023

WIREs Mechanisms of Disease

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Transcription factors are crucial to regulate gene expression in immune cells and in other cell types. In lymphocytes, there are a large number of different transcription factors that are known to contribute to cell differentiation and the balance between quiescence and activation. One such transcription factor is E26 oncogene homolog 1 (Ets1). Ets1 expression is high in quiescent B and T lymphocytes and its levels are decreased upon activation. The human ETS1 gene has been identified as a susceptibility locus for many autoimmune and inflammatory diseases. In accord with this, gene knockout of Ets1 in mice leads to development of a lupus‐like autoimmune disease, with enhanced activation and differentiation of both B cells and T cells. Prior reviews have summarized functional roles for Ets1 based on studies of Ets1 knockout mice. In recent years, numerous additional studies have been published that further validate ETS1 as a susceptibility locus for human diseases where immune dysregulation plays a causative role. In this update, new information that further links Ets1 to human autoimmune diseases is organized and collated to serve as a resource. This update also describes recent studies that seek to understand molecularly how Ets1 regulates immune cell activation, either using human cells and tissues or mouse models. This resource is expected to be useful to investigators seeking to understand how Ets1 may regulate the human immune response, particularly in terms of its roles in autoimmunity and inflammation.This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Molecular and Cellular Physiology

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Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 64%

Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 99%

Section: Autoimmune and Inflammatory Phenotypes In Ets1 Knockout Micementioning

confidence: 99%

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An update on the roles of transcription factor Ets1 in autoimmune diseases

Garrett‐Sinha

2023

WIREs Mechanisms of Disease

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“…Genome topology, which is organized at various length scales from megabase-scale compartments and topologically associating domains (TADs) to fine-scale chromatin loops, contributes to spatial positioning of enhancers and their target promoters, influencing their activity and specificity 6, 7, 8, 9 . Given that the number of active enhancers is 2-3 times more than active genes 10 , it is often possible that multiple enhancers control the expression of a single gene, giving rise to complex enhancer regulatory circuits 11, 12, 13 . Although chromatin interaction data alone cannot capture the complexity of potential multi-enhancer regulation, its integration with chromatin activity datasets at a few oncogenes revealed that multiple distal enhancers can spatially cluster with promoters to form enhancer-promoter hubs in cancer genomes 3, 14, 15, 16, 17 .…”

Section: Introductionmentioning

confidence: 99%

“…Although chromatin interaction data alone cannot capture the complexity of potential multi-enhancer regulation, its integration with chromatin activity datasets at a few oncogenes revealed that multiple distal enhancers can spatially cluster with promoters to form enhancer-promoter hubs in cancer genomes 3, 14, 15, 16, 17 . More recent studies have demonstrated that enhancer-promoter hubs facilitate enhancer cooperativity and target specificity to control gene expression dosage 12, 14, 18 . Despite these advances, a systematic understanding of enhancer-promoter hub prevalence, organization principles, and regulatory importance in mediating oncogenic enhancer function is lacking.…”

Section: Introductionmentioning

confidence: 99%

Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance

Perlman,

Burget,

Zhou

et al. 2024

Preprint

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SUMMARYRecent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remains unclear. Here, we systematically identified enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We found that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further showed that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance.

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