Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes

Ringel, Alessa; Szabo, Quentin; Chiariello, Andrea M.; Chudzik, Konrad; Schöpflin, Robert; Rothe, Patricia; Mattei, Alexandra L.; Zehnder, Tobias; Harnett, Dermot; Laupert, Verena; Bianco, Simona; Hetzel, Sara; Glaser, Juliane; Phan, Mai H Q; Schindler, Magdalena; Ibrahim, Daniel M.; Paliou, Christina; Esposito, Andrea; Prada-Medina, César Augusto; Haas, Stefan A.; Giere, Peter; Vingron, Martin; Wittler, Lars; Meissner, Alexander; Nicodemi, Mario; Cavalli, Giacomo; Bantignies, Frédéric; Mundlos, Stefan; Robson, Michael I.

doi:10.1016/j.cell.2022.09.006

Cited by 33 publications

(23 citation statements)

References 156 publications

(246 reference statements)

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“…To change Fgf9 activity, a chromosomal rearrangement, affecting the distal part of the Fgf9 TAD, occurred in moles. Given TADs role in insulating a regulatory pattern, they ensure an integration of a newly established gene or a change in regulation to occur without huge alterations in neighborhood 64 . Thus, the regulatory context provided by TADs is an important object for the evolution of organisms.…”

Section: Discussionmentioning

confidence: 99%

TAD border deletion at theKitlocus causes tissue-specific ectopic activation of a neighboring gene

Kabirova

Ryzhkova

Lukyanchikova

et al. 2022

Preprint

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Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation, a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.

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Section: Discussionmentioning

confidence: 99%

TAD border deletion at theKitlocus causes tissue-specific ectopic activation of a neighboring gene

Kabirova

Ryzhkova

Lukyanchikova

et al. 2022

Preprint

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“…However, intrinsic E-P compatibility appears to play a lesser role in mammals where most enhancers activate all promoters by similar amounts (Bergman et al 2022;Martinez-Ara et al 2022;Zabidi et al 2014). Another potential mechanism for achieving divergent gene expression patterns within the same TAD could be promoter repression via CpG methylation, as was recently shown in the mouse Rex1/Fat1 locus (Ringel et al 2022). Our analysis of remote E-P interactions shows that promoters of skipped genes are often inactive, methylated, and inaccessible (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…How is this E-P selectivity achieved in mammalian genomes? A recent study on a single mouse Rex1/Fat1 locus suggests that promoter repression through DNA methylation may result in an intra-TAD E-P specificity (Ringel et al 2022). To test if this mechanism is 5 generally utilized at other developmental loci, we systematically assessed the chromatin state of skipped promoters.…”

Section: Long-range Enhancer-promoter Specificity Is Linked To Repres...mentioning

confidence: 99%

Increased Enhancer-Promoter Interactions during Developmental Enhancer Activation in Mammals

Chen

Snetkova

Bower

et al. 2022

Preprint

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Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Although some enhancer-promoter loops are cell-type-specific, others are stable across tissues or even display reduced physical proximity upon activation. A major challenge is that relatively few enhancers are functionally characterized in vivo, making it difficult to draw generalized conclusions about enhancer-promoter looping during developmental gene activation. Here, we investigate the 3D conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand mammalian enhancers with known in vivo activities in ten murine embryonic tissues. We performed enhancer knockouts in mice, which validated newly identified enhancer-promoter chromatin interactions. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are significantly stronger upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, corresponding enhancers still display highly-tissue-specific activities indicating that their activity is uncoupled from a chromatin interaction with promoters. We find that these invariant interactions form in the absence of the enhancer and are mediated by adjacent CTCF binding. We also identified putative in vivo target genes for enhancers linked to congenital malformations, neurodevelopmental disorders, and autism, demonstrating the utility of our dataset for understanding human congenital disorders. Our results highlight the general significance of enhancer-promoter physical proximity for developmental gene activation in mammals.

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“…Specifically, the depletion of cohesin subtly reduces enhancer–promoter contacts and leads to a small decrease in gene expression, but CTCF depletion can induce rewiring of interactions and ectopic gene activation in some cases, instead of generally reducing interactions between certain enhancers and promoters [70] . Furthermore, a recent study showed that a TAD physically separates Zfp42 and Fat1 , which have distinct local enhancers that drive their independent expression in ESCs (embryonic stem cells), but this separation is driven by chromatin activity independent of CTCF/cohesion [71] .…”

Section: Topological Insulators and Chromatin Mediators As A Function...mentioning

confidence: 99%

Novel biological insights revealed from the investigation of multiscale genome architecture

Ding¹,

Zhang²

2023

Computational and Structural Biotechnology Journal

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Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes

Cited by 33 publications

References 156 publications

TAD border deletion at theKitlocus causes tissue-specific ectopic activation of a neighboring gene

TAD border deletion at theKitlocus causes tissue-specific ectopic activation of a neighboring gene

Increased Enhancer-Promoter Interactions during Developmental Enhancer Activation in Mammals

Novel biological insights revealed from the investigation of multiscale genome architecture

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