The Hoxd Cluster Is a Dynamic and Resilient Tad Boundary Controlling the Segregation of Antagonistic Regulatory Landscapes

Rodríguez-Carballo, Eddie; Lopez-Delisle, Lucille; Ye, Zhan; Fabre, Pierre J.; Beccari, Léonardo; El-Idrissi, Imane; Huynh, Thi Hahn Nguyen; Özadam, Hakan; Dekker, Job; Duboule, Denis

doi:10.1101/193706

Cited by 55 publications

(97 citation statements)

References 92 publications

(142 reference statements)

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“…We found that deleting any individual CTCF site minimally altered predictions. Our model thus predicts this boundary is formed by redundant CTCF sites, a phenomenon observed experimentally in other genomic locations 3,4 .…”

supporting

confidence: 58%

Predicting 3D genome folding from DNA sequence

Fudenberg

Kelley

Pollard

2019

Preprint

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In interphase, the human genome sequence folds in three dimensions into a rich variety of locus-specific contact patterns. Here we present a deep convolutional neural network, Akita, that accurately predicts genome folding from DNA sequence alone. Representations learned by Akita underscore the importance of CTCF and reveal a complex grammar underlying genome folding. Akita enables rapid in silico predictions for sequence mutagenesis, genome folding across species, and genetic variants. Main textRecent research has advanced our understanding of the proteins driving and the sequences underpinning 3D genome folding in mammalian interphase, including the interplay between CTCF and cohesin 1 , and their roles in development and disease 2 . Still, while disruptions of single bases can alter genome folding, in other cases genome folding is surprisingly resilient to large-scale deletions and structural variants 3,4 . As follows, predicting the consequences of perturbing any individual CTCF site, or other regulatory element, on local genome folding remains a challenge.Previous machine learning approaches have either: (1) relied on epigenomic information as inputs 5-7 , which does not readily allow for predicting effects of DNA variants, or (2) predicted derived features of genome folding (e.g. peaks 8,9 ), which depend heavily on minor algorithmic differences 10 . Making quantitative predictions from sequence poses a substantial challenge: base pair information must be propagated to megabase scales where locus-specific patterns become salient in chromosome contact maps.Convolutional neural networks (CNNs) have emerged as powerful tools for modelling genomic data as a function of DNA sequence, directly learning DNA sequence features from the data. CNNs now make state-of-the-art predictions for transcription factor binding, DNA accessibility, transcription, and RNA-binding [11][12][13][14] . DNA sequence features learned by CNNs can be subsequently post-processed into interpretable forms 15 . Recently, Basenji 16 demonstrated that CNNs can process very long sequences (~131kb) to learn distal regulatory element influences, suggesting that genome folding could be tractable with CNNs.Here we present Akita, a deep CNN to transform input DNA sequence into predicted locusspecific genome folding. Akita takes in ~1Mb (2 20 bp) of DNA sequence and predicts contact

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supporting

confidence: 58%

Predicting 3D genome folding from DNA sequence

Fudenberg

Kelley

Pollard

2019

Preprint

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“…Nevertheless, this property of structural variants can be beneficial for characterizing the chromatin landscape if disruptions of multiple elements, e.g. bound CTCF sites, are required to alter the boundary activity of TADs, as appears to be the case at the HoxD locus (Rodríguez-Carballo et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Chromatin features constrain structural variation across evolutionary timescales

Fudenberg

Pollard

2018

Preprint

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Abstract:The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of non-coding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via 'enhancer hijacking', whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.

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“…TADs have therefore been proposed to act as functional regulatory units that favour contacts between enhancers and their target gene within a TAD whilst limiting aberrant interactions of enhancers across TAD boundaries (Fudenberg et al, 2016;Sun et al, 2019). In support of this, some studies have found that deletion or inversion of CTCF sites at TAD boundaries, can promote TAD boundary crosstalk and re-wire enhancer-promoter contacts (de Wit et al, 2015;Guo et al, 2015;Narendra et al, 2015;Rodríguez-Carballo et al, 2017). Moreover, a number of recent studies have suggested that changes to TAD structure can disrupt gene regulation through enhancer-rewiring in human disease (Flavahan et al, 2016;Franke et al, 2016;Lupiáñez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Developmentally regulated Shh expression is robust to TAD perturbations

Williamson

Kane

Devenney

et al. 2019

Preprint

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Topologically Associating Domains (TADs) have been proposed to both guide and constrain enhancer activity. Shh is located within a TAD known to contain all its enhancers. To investigate the importance of chromatin conformation and TAD integrity on developmental gene regulation, we have manipulated the Shh TAD -creating internal deletions, deleting CTCF sites including those at TAD boundaries, as well as larger deletions and inversions of TAD boundaries. Chromosome conformation capture and fluorescence in situ hybridisation assays were used the investigate changes in chromatin conformation that result from these manipulations. Our data suggest that the substantial alteration of TAD structure has no readily detectable effect on Shh expression patterns during development -except where enhancers are deleted -and results in no detectable phenotypes. Only in the case of a larger deletion of one TAD boundary could some ectopic influence of the Shh limb enhancer be detected on a gene -Mnx1 in the neighbouring TAD. Our data suggests that, contrary to expectations, the developmental regulation of Shh expression is remarkably robust to TAD perturbations. oncogene activation in IDH mutant gliomas. Nature 529, 110-114.

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The Hoxd Cluster Is a Dynamic and Resilient Tad Boundary Controlling the Segregation of Antagonistic Regulatory Landscapes

Cited by 55 publications

References 92 publications

Predicting 3D genome folding from DNA sequence

Predicting 3D genome folding from DNA sequence

Chromatin features constrain structural variation across evolutionary timescales

Developmentally regulated Shh expression is robust to TAD perturbations

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