Epromoters function as a hub to recruit key transcription factors required for the inflammatory response

Santiago-Algarra, David; Souaid, Charbel; Singh, Himanshu Narayan; Dao, Lan T M; Hussain, Saadat; Medina-Rivera, Alejandra; Ramirez-Navarro, Lucia; Castro-Mondragón, Jaime A; Sadouni, Nori; Charbonnier, Guillaume; Spicuglia, Salvatore

doi:10.1038/s41467-021-26861-0

Cited by 23 publications

(30 citation statements)

References 83 publications

(136 reference statements)

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“…For 75% of the ISG promoters with a co-accessibly link, the distal STAT1/2 bound site was at another ISG promoter, whereas the remaining 25% were at a bona fide enhancer. This points to a co-regulation between ISG promoter elements that is supported by a recent report showing that also promoters can act as enhancers to drive expression of ISG clusters ( Santiago-Algarra et al, 2021 ). In addition, our data suggest that IFNβ induction and STAT1/2 binding could also involve the removal of preexisting inhibitory links between ISGs and distal regulatory regions.…”

Section: Discussionsupporting

confidence: 55%

Epigenetic signals that direct cell type–specific interferon beta response in mouse cells

et al. 2023

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The antiviral response induced by type I interferon (IFN) via the JAK-STAT signaling cascade activates hundreds of IFN-stimulated genes (ISGs) across human and mouse tissues but varies between cell types. However, the links between the underlying epigenetic features and the ISG profile are not well understood. We mapped ISGs, binding sites of the STAT1 and STAT2 transcription factors, chromatin accessibility, and histone H3 lysine modification by acetylation (ac) and mono-/tri-methylation (me1, me3) in mouse embryonic stem cells and fibroblasts before and after IFNβ treatment. A large fraction of ISGs and STAT-binding sites was cell type specific with promoter binding of a STAT1/2 complex being a key driver of ISGs. Furthermore, STAT1/2 binding to putative enhancers induced ISGs as inferred from a chromatin co-accessibility analysis. STAT1/2 binding was dependent on the chromatin context and positively correlated with preexisting H3K4me1 and H3K27ac marks in an open chromatin state, whereas the presence of H3K27me3 had an inhibitory effect. Thus, chromatin features present before stimulation represent an additional regulatory layer for the cell type–specific antiviral response.

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Section: Discussionsupporting

confidence: 55%

Epigenetic signals that direct cell type–specific interferon beta response in mouse cells

et al. 2023

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“…observed enhancer combinations), not finding certain combinations of enhancers in at least one cell does not mean they do not occur, since single cell technology -even when considering >20k cellsmay not identify co-active enhancers below certain detection levels. Moreover, some enhancer regulatory patterns may only be revealed under particular cellular contexts or stresses, as has been demonstrated in recent studies of context-dependent quantitative trait loci (QTL) and reporter assays [34][35][36][37][38] . The use of larger datasets of multimodal single cell data, as well as exploring context-dependent effects and other cell-types would likely allow us to observe more enhancer activity combinations.…”

Section: Discussionmentioning

confidence: 99%

Widespread enhancer co-activity identified by multimodal single cell analysis

Ziyani

Delaneau

Ribeiro

2022

Preprint

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Non-coding regulatory elements such as enhancers are key in controlling the cell type-specificity and spatio-temporal expression of genes. To drive stable and precise gene transcription that is robust to genetic variation and environmental stress, genes are often targeted by multiple enhancers with redundant action. However, it is unknown whether enhancers targeting the same gene display simultaneous activity or whether some enhancer combinations are more often co-active than others. Here, we take advantage of the recent developments in single cell technology that permit assessing chromatin status (scATAC-seq) and gene expression (scRNA-seq) in the same single cells to link gene expression to the activity of multiple enhancers. Measuring activity patterns across 24,844 human lymphoblastoid single cells, we found that the majority of enhancers associated with the same gene display significant correlation in their chromatin profiles. For 6944 expressed genes associated with enhancers, we identified 89,885 significant enhancer-enhancer associations between nearby enhancers. We found that associated enhancers share similar transcription factor binding profiles and that gene essentiality is linked with higher enhancer co-activity. Our extensive enhancer co-activity maps can be used to pinpoint combinations of enhancers relevant in gene expression regulation and allow us to better predict the effect of genetic variation falling in non-coding regions.

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“…Moreover, enhancers have been shown to be a possible substrate for the origin of new genes (Carelli et al, 2018; Majic and Payne, 2020) and it is also possible that the essentiality retrieved from CRISPR screens is actually capturing the essentiality of the regulatory role of the genomic regions. Indeed, promoters with enhancer function (ePromoters) of interferon signalling response have been shown to be more conserved than other non-enhancer genes belonging to the same pathway (Santiago-Algarra et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary analysis of gene ages across TADs associates chromatin topology with whole genome duplications

James

Trevisán-Herraz

Rico

2021

Preprint

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Topologically associated domains (TADs) are interaction sub-networks of 3D genomes. TAD boundaries frequently coincide with genome breaks while their deletion is under negative selection, suggesting that TADs act as modules facilitating genome rearrangements and metazoan evolution. However, the role of TADs in the evolution of gene regulation and essentiality is not well understood. Here, we show that TADs play a role organising ancestral functions and evolutionary novelty. We discovered that genes co-localise by evolutionary age in the human and mouse genomes, resulting in TADs that have different proportions of younger and older genes. A major transition in the TAD age co-localisation patterns is observed between the genes born as a result of the vertebrate whole genome duplications (WGDs) or before, and those born afterwards. We also found that primate- and rodent-specific genes are more frequently essential when they are located in 'aged' TADs and connected to genes that have not duplicated since the WGD. Our data suggests that evolutionary success of recent genes may increase when located in functionally relevant TADs with established regulatory networks.

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Epromoters function as a hub to recruit key transcription factors required for the inflammatory response

Cited by 23 publications

References 83 publications

Epigenetic signals that direct cell type–specific interferon beta response in mouse cells

Epigenetic signals that direct cell type–specific interferon beta response in mouse cells

Widespread enhancer co-activity identified by multimodal single cell analysis

Evolutionary analysis of gene ages across TADs associates chromatin topology with whole genome duplications

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