To loop or not to loop: what is the role of TADs in enhancer function and gene regulation?

Cavalheiro, Gabriel R.; Pollex, Tim; Furlong, Eileen E. M.

doi:10.1016/j.gde.2020.12.015

Cited by 67 publications

(63 citation statements)

References 85 publications

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“…While experiments that perturb chromatin structure by deleting TAD borders have reported large (over 8-fold) changes in gene expression ( Cavalheiro et al, 2021 ; McCord et al, 2020 ; Figure 1—figure supplement 4 ), experiments that globally abrogated TADs by depleting cohesin observed few genes changing expression by more than 2-fold ( Rao et al, 2014 ; Zuin et al, 2014 ; Figure 5A, B ). As these experiments differ by orders of magnitude in the time scale at which transcription changes are assessed (due to technical limitations), we wanted to explore the temporal behavior of the futile cycle promoters by assessing the effect of a TAD boundary deletion/fusion at an early time point relative to a late time point.…”

Section: Resultsmentioning

confidence: 99%

“…(C) Cartoon representation of the "lock and key" explanation of enhancer-promoter specificity, contrasted with the "tipping point" explanation suggested by results in (B). Hysteresis in promoter activation leads to a unique response at different timescales While experiments which perturb chromatin structure by deleting TAD borders have reported large (over 8-fold) changes in gene expression (Cavalheiro et al, 2021;McCord et al, 2020) ( Fig. 1 supplement 4), experiments which globally abrogated TADs by depleting cohesin observed few genes changing expression by more than two-fold (Rao et al, 2014;Zuin et al, 2014) (Fig.…”

Section: Promoter-specific Properties Can Create An Illusion Of Enhancer-promoter Specificitymentioning

confidence: 99%

“…However, recent microscopy experiments uncovered little correlation between enhancer-promoter (E-P) proximity and nascent transcription activity at well-studied loci ( Alexander et al, 2019 ; Mateo et al, 2019 ) reviewed in Finn and Misteli, 2019b . This surprising disagreement has led to various speculative explanations, such as action at a distance through condensates with diameters of tens of molecules ( Alexander et al, 2019 ; Benabdallah et al, 2019 ; Cavalheiro et al, 2021 ; Heist et al, 2019 ; Lim and Levine, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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How subtle changes in 3D structure can create large changes in transcription

Xiao

Hafner

Boettiger

2021

eLife

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Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than two-fold, even though disruptions of TAD borders can change gene expression by ten-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between enhancer-promoter contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

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Section: Resultsmentioning

confidence: 99%

Section: Promoter-specific Properties Can Create An Illusion Of Enhancer-promoter Specificitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How subtle changes in 3D structure can create large changes in transcription

Xiao

Hafner

Boettiger

2021

eLife

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“…At a large scale within nuclei, chromosomes segregate into regions of preferential long-range interactions that form two mutually excluded types of chromatin, referred to as “A” and “B” compartments [ 125 ], the formation of which has been recently linked to homotypic clustering of L1 and B1/Alu, respectively [ 126 ]. At a scale of tens to hundreds of kilobases, chromosomes fold into domains with preferential intradomain interactions known as topologically associating domains (TADs), which harbor the potential to influence enhancer function and thus gene regulatory networks [ 127 , 128 , 129 , 130 , 131 , 132 ]. TAD demarcation is achieved by specific regions called TAD boundaries, which are enriched for the occupancy of CCCTC-binding factor (CTCF), a zinc finger DNA binding protein also known to mediate the formation of chromatin loops [ 133 ].…”

Section: Retrotransposons and Their Impact On Mammalian Genome Evolutionmentioning

confidence: 99%

Retrotransposons as Drivers of Mammalian Brain Evolution

Ferrari

Grandi

Tramontano

et al. 2021

Life

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Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocortex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function.

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“…However, there is also significant evidence questioning the role of the chromatin structure modulating gene expression [ 133 , 137 ]. In Drosophila , the analysis of gene expression in balancers (highly rearranged chromosomes) showed that disruption of TADs has little effect on gene activity and only a subset of genes is sensitive to structural alterations [ 138 ].…”

Section: Functional Organization Of the Genomementioning

confidence: 99%

Chromatin Organization and Function in Drosophila

Llorens-Giralt

Camilleri-Robles

Corominas

et al. 2021

Cells

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Eukaryotic genomes are packaged into high-order chromatin structures organized in discrete territories inside the cell nucleus, which is surrounded by the nuclear envelope acting as a barrier. This chromatin organization is complex and dynamic and, thus, determining the spatial and temporal distribution and folding of chromosomes within the nucleus is critical for understanding the role of chromatin topology in genome function. Primarily focusing on the regulation of gene expression, we review here how the genome of Drosophila melanogaster is organized into the cell nucleus, from small scale histone–DNA interactions to chromosome and lamina interactions in the nuclear space.

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To loop or not to loop: what is the role of TADs in enhancer function and gene regulation?

Cited by 67 publications

References 85 publications

How subtle changes in 3D structure can create large changes in transcription

How subtle changes in 3D structure can create large changes in transcription

Retrotransposons as Drivers of Mammalian Brain Evolution

Chromatin Organization and Function in Drosophila

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