Breaking TADs: How Alterations of Chromatin Domains Result in Disease

Lupiáñez, Darío G.; Spielmann, Malte; Mundlos, Stefan

doi:10.1016/j.tig.2016.01.003

Cited by 369 publications

(316 citation statements)

References 97 publications

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“…Compelling examples were recently published in which 3C studies decisively helped to unravel the molecular mechanisms underlying disease (Lupianez et al 2016).…”

Section: Explaining Disease In the 3d Genomementioning

confidence: 99%

The second decade of 3C technologies: detailed insights into nuclear organization

2016

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The relevance of three-dimensional (3D) genome organization for transcriptional regulation and thereby for cellular fate at large is now widely accepted. Our understanding of the fascinating architecture underlying this function is based on microscopy studies as well as the chromosome conformation capture (3C) methods, which entered the stage at the beginning of the millennium. The first decade of 3C methods rendered unprecedented insights into genome topology. Here, we provide an update of developments and discoveries made over the more recent years. As we discuss, established and newly developed experimental and computational methods enabled identification of novel, functionally important chromosome structures. Regulatory and architectural chromatin loops throughout the genome are being cataloged and compared between cell types, revealing tissue invariant and developmentally dynamic loops. Architectural proteins shaping the genome were disclosed, and their mode of action is being uncovered. We explain how more detailed insights into the 3D genome increase our understanding of transcriptional regulation in development and misregulation in disease. Finally, to help researchers in choosing the approach best tailored for their specific research question, we explain the differences and commonalities between the various 3C-derived methods.

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“…Compelling examples were recently published in which 3C studies decisively helped to unravel the molecular mechanisms underlying disease (Lupianez et al 2016).…”

Section: Explaining Disease In the 3d Genomementioning

confidence: 99%

The second decade of 3C technologies: detailed insights into nuclear organization

2016

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“…Moreover, the mother does not have conspicuous facial features, which is concordant with the fact that the 7q11.23 inversion may not involve severe clinical symptoms [Tam et al, 2008]. However, it has been recently demonstrated that the disruption of the 'topologically associating domain', i.e., distant and separated regions of the genome that share the same enhancers, promoters, and transcriptional machinery by chromosomal rearrangements, can cause gene misexpression and disease [Lupiáñez et al, 2016]. Thus, this situation could explain the clinical suspicion of a lower IQ but a normal physical phenotype in the mother.…”

Section: Discussionmentioning

confidence: 65%

Distal 7q11.23 Duplication, an Emerging Microduplication Syndrome: A Case Report and Further Characterisation

et al. 2016

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Chromosome 7q11.23 duplication syndrome is a well-recognised syndrome which involves the duplication of the same genes located in the Williams-Beuren critical region. However, in 2010, 4 patients were reported with a microduplication only in the HIP1 and YWHAG genes. We refer to this as a distal 7q11.23 duplication (dup7q11.23D). Here, we report the fifth de novo patient with dup7q11.23D, whose symptoms may be explained by YWHAG overexpression as was demonstrated recently in mice and obese patients. Finally, further studies will be necessary to delineate this emerging microduplication syndrome.

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“…22 Different juxtapositions of transcription factories, enhancers, and promoters interact with each other in physical space, giving rise to differential expression patterns. 23,24 Such variation in chromosomal conformation is not only found among different organisms, but is also observed among different tissues of the same organism. Distinct cell types exhibit unique 3D chromatin structures and genome topology.…”

Section: Chromosomal Conformation Codementioning

confidence: 99%

“…25 Altering the structure of TADs and boundaries can lead to diseases. 24 Notably, 3D genome structure modifications play a central role in cell identity determination for other mechanisms such as transcriptional and epigenetic control, the details of which will be expanded in the following sections.…”

Section: Chromosomal Conformation Codementioning

confidence: 99%

Cellular identity at the single-cell level

2016

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A single cell creates surprising heterogeneity in a multicellular organism. While every organismal cell shares almost an identical genome, molecular interactions in cells alter the use of DNA sequences to modulate the gene of interest for specialization of cellular functions. Each cell gains a unique identity through molecular coding across the DNA, RNA, and protein conversions. On the other hand, loss of cellular identity leads to critical diseases such as cancer. Most cell identity dissection studies are based on bulk molecular assays that mask differences in individual cells. To probe cell-to-cell variability in a population, we discuss single cell approaches to decode the genetic, epigenetic, transcriptional, and translational mechanisms for cell identity formation. In combination with molecular instructions, the physical principles behind cell identity determination are examined. Deciphering and reprogramming cellular types impact biology and medicine.

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Breaking TADs: How Alterations of Chromatin Domains Result in Disease

Cited by 369 publications

References 97 publications

The second decade of 3C technologies: detailed insights into nuclear organization

The second decade of 3C technologies: detailed insights into nuclear organization

Distal 7q11.23 Duplication, an Emerging Microduplication Syndrome: A Case Report and Further Characterisation

Cellular identity at the single-cell level

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