The 3D Genome Shapes the Regulatory Code of Developmental Genes

Mozziconacci, Julien; Merle, Mélody; Lesne, Annick

doi:10.1016/j.jmb.2019.10.017

Cited by 9 publications

(4 citation statements)

References 89 publications

(106 reference statements)

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“…The importance of TADs and the effect of TAD border disruption (dashed arrow in Fig. 1 ) have also been shown in the case of Hox genes [ 25 ], or as a way to control developmental genes in drosophila embryos, as we recently proposed [ 26 ]. An effect of TAD border disruption has also been observed in cancer cells as a consequence of cancerous mutations [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 56%

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

et al. 2022

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Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.

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Section: Introductionmentioning

confidence: 56%

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

et al. 2022

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“…Gene misregulation can occur due to TAD border disruption induced by the presence of short tandem repeats [27]. The importance of TADs and the effect of TAD border disruption (dashed arrow in Fig 1) has also been shown in the case of Hox genes [28,29], or as a way to control developmental genes in drosophila embryos, as we recently proposed [30]. An effect of TAD border disruption has also been observed in cancer cells as a consequence of cancerous mutations [31,32].…”

Section: Introductionmentioning

confidence: 68%

Contribution of 3D genome topological domains to genetic risk of cancers

Jablonski

Carron

Mozziconacci

et al. 2021

Preprint

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Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases display such a preferential location of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that TAD border enrichment in risk loci differ between cancers and non-cancer diseases. Different TAD border enrichments are observed in embryonic stem cells and differentiated cells, which agrees with an evolution along embryogenesis of the 3D genome organization into topological domains. Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization.

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“…At the genesis of the genetic code, Crick [26] introduced an abstract representation based on codes, adapters, and objects, to provide a theoretical framework explaining how the genetic information is converted into proteins. Mozziconacci et al [27] propose a similar semantic code to understand the roles of transcription factors and 3D TAD folding in the regulation of transcription. In this inspiring analogy, transcription factors represent code words, while the role of adapters is played by the specific set of promoters, enhancers, and insulators that, when occupied by the right set of transcription factors will lead to active transcription.…”

Section: Editorial Overviewmentioning

confidence: 99%