Modulated contact frequencies at gene-rich loci support a statistical helix model for mammalian chromatin organization

Court, Franck; Miro, Julie; Braem, Caroline; Lelay-Taha, Marie-Noëlle; Brisebarre, Audrey; Atger, Florian; Gostan, Thierry; Weber, Michaël; Cathala, Guy; Forné, Thierry

doi:10.1186/gb-2011-12-5-r42

Cited by 22 publications

(37 citation statements)

References 35 publications

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“…TADs existence and distribution, as well as the genome segregation into active and inactive compartments have been unraveled using genome-wide Hi-C. TADs organize the genome into a modular and presumably functional structure at the sub-megabase scale [37]. Chromatin loops and TADs have also been investigated experimentally using local quantitative and high-resolution chromosome conformation capture technique (3C-qPCR) [38,39]. Such experiments using 3C-qPCR clarified the distinction between the TADs as originally evidenced in [34] and [35], of size 200 kb to 1Mb (median size about 800 kb) and structures of various sizes termed chromosome contact domains [40], among which the smallest ones rather correspond to chromatin loops embedding a single gene and its proximal regulatory sequences [41].…”

Section: Different Relationships To Diseasementioning

confidence: 99%

Genome supranucleosomal organization and genetic susceptibility to diseases

Jablonski

Fretter

Carron

et al. 2017

AIP Conference Proceedings

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The notion of disease-associated single-nucleotide polymorphisms (da-SNP), as determined in genome-wide association studies (GWAS), is relevant for many complex pathologies, including cancers. It appeared that da-SNPs are not only markers of causal genetic variation but may contribute to the disease development through an influence on gene expression levels. We argue that understanding this possible functional role of da-SNPs requires to consider their embedding in the tridimensional (3D) multi-scale organization of the human genome. We then focus on the potential impact of da-SNPs on chromatin loops and recently observed topologically associating domains (TADs). We show that for some diseases and cancer types, da-SNPs are over-represented in the borders of these topological domains, in a way that cannot be explained by an increased exon density. This analysis of the distribution of da-SNPs within the 3D genome organization suggests candidate loci for further experimental investigation of the mechanisms underlying genetic susceptibility to diseases, in particular cancer. Recently developed techniques of chromosome conformation capture combine chemical crosslinking and sequencing to identify genomic loci contacting each other in vivo. They have shown that the mammalian genome displays three main architectural features at the large-scale level (supranucleosomal level, beyond the kb scale), nested in a hierarchical way (Figure 2): chromatin loops, topologically associating domains (TADs) of larger size exhibiting more internal contacts than contacts between domains [34, 35], and a segregation in active and inactive compartments [36].

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Section: Different Relationships To Diseasementioning

confidence: 99%

Genome supranucleosomal organization and genetic susceptibility to diseases

Jablonski

Fretter

Carron

et al. 2017

AIP Conference Proceedings

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“…range locus-specific interactions, the mammalian chromatin tends to adopt statistically a helix shape [16]. If we depict the mouse Igf2/H19 locus in the context of the statistical helix, Fig.…”

Section: Experimental Validationmentioning

confidence: 99%

Chromatin fiber allostery and the epigenetic code

Lesne

Foray

Cathala

et al. 2015

J. Phys.: Condens. Matter

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Abstract. The notion of allostery introduced for proteins about fifty years ago has been extended since then to DNA allostery, where a locally triggered DNA structural transition remotely controls other DNA-binding events. We further extend this notion and propose that chromatin fiber allosteric transitions, induced by histone-tail covalent modifications, may play a key role in transcriptional regulation. We present an integrated scenario articulating allosteric mechanisms at different scales: allosteric transitions of the condensed chromatin fiber induced by histone-tail acetylation modify the mechanical constraints experienced by the embedded DNA, thus possibly controlling DNA-binding of allosteric transcription factors or further allosteric mechanisms at the linker DNA level. At a higher scale, different epigenetic constraints delineate different statistically dominant subsets of accessible chromatin fiber conformations, which each favors the assembly of dedicated regulatory complexes, as detailed on the emblematic example of the mouse Igf2-H19 gene locus and its parental imprinting. This physical view offers a mechanistic and spatially structured explanation of the observed correlation between transcriptional activity and histone modifications. The evolutionary origin of allosteric control supports to speak of an "epigenetic code", by which events involved in transcriptional regulation are encoded in histone modifications in a context-dependent way.

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“…The 3C-qPCR assay was performed as described (Hagège et al 2007) with the following modifications (Court et al 2011). The 3 3 10 7 COLO829 cells that were stably transduced with control or MITF knockdown vectors, or transient TALEN treatment, were crosslinked with 1% formaldehyde at room temperature for 10 min, followed by glycine quenching and cell lysis.…”

Section: Chromosome Conformation Capture (3c) Assaymentioning

confidence: 99%

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

et al. 2014

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Thousands of putative enhancers are characterized in the human genome, yet few have been shown to have a functional role in cancer progression. Inhibiting oncokinases, such as EGFR, ALK, ERBB2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by up-regulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific enhancers at the MET locus for multiple common tumor types, including a melanoma lineage-specific enhancer 63 kb downstream from the MET TSS. This enhancer displays inducible chromatin looping with the MET promoter to up-regulate MET expression upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7 bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro-and antioncogenic functions of a dominant transcription factor and block innate resistance to oncokinase therapy.

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Modulated contact frequencies at gene-rich loci support a statistical helix model for mammalian chromatin organization

Cited by 22 publications

References 35 publications

Genome supranucleosomal organization and genetic susceptibility to diseases

Genome supranucleosomal organization and genetic susceptibility to diseases

Chromatin fiber allostery and the epigenetic code

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

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