4D Genome Architecture in Disease Associated Mutations

We are interested in disease mechanisms induced by alterations in the 3D chromatin conformation of the genome. So far, the non-coding genome has not been the focus of human genetics and Mendelian disease research on non-coding variants is only slowly emerging. This is mainly due to a large number of variants per genome and difficulties in interpreting non-coding variants. Together, this poses major problems that partially require the use of other/new technologies as well as new concepts of thinking and data interpretation. Our lab focuses on elucidating the pathomechanisms underlying disease-causing mutations in the non-coding genome.

We recently showed that deletions, duplications, inversions, translocations and insertions, collectively called structural variations (SVs) can result in disease-causing re-wiring of enhancer-promoter contacts by changing the regulatory architecture of the locus. In particular, we are investigating the effect of SVs on TAD configuration and gene expression during development.

Since there is currently no general concept to interpret mutations in the non-coding genome for their ability to cause disease, it is the aim of our group to develop such a framework and predict the regulatory effect of SVs in a disease setting.

The strength of our research lies in the tight interplay between our focus on basic research in gene regulation and the screening of large patient cohorts with limb malformations via array-CGH and whole genome sequencing. Using these methods we have identified a series of structural variations involving Conserved Non-coding Elements (CNEs) that are located in the vicinity of developmentally important genes. This includes deletions, duplications, and inversions at the BMP2 (brachydactyly type A2), SHH (mirror-image polydactyly), SOX9 (Cooks syndrome), IHH (craniosynostosis with syndactyly), MSX2 (cleidocranial dysplasia), and PITX1 (Liebenberg Syndrome) loci. Collectively, our research emphasises the role of altered gene regulation caused by structural variations as a disease-causing mechanism for a variety of Mendelian diseases.

Selected Publications

Kragesteen BK, Spielmann M, Paliou C, Heinrich V, Schöpflin R, Esposito A, Annunziatella C, Bianco S, Chiariello AM, Jerković I, Harabula I, Guckelberger P, Pechstein M, Wittler L, Chan WL, Franke M, Lupiáñez DG, Kraft K, Timmermann B, Vingron M, Visel A, Nicodemi M, Mundlos S, Andrey G.
Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis.
Nat Genet. 2018 Oct;50(10):1463-1473. Epub 2018 Sep 27.
Spielmann M, Lupiáñez DG, Mundlos S.
Structural variation in the 3D genome.
Nat Rev Genet. 2018 Jul;19(7):453-467. Review.
Bianco S, Lupiáñez DG, Chiariello AM, Annunziatella C, Kraft K, Schöpflin R, Wittler L, Andrey G, Vingron M, Pombo A, Mundlos S, Nicodemi M.
Polymer Physics Predicts the Effects of Structural Variants on Chromatin Architecture
Nat Genet. 2018 May;50(5):662-667. Epub 2018 Apr 16.
Andrey G, Mundlos S.
The three-dimensional genome: regulating gene expression during pluripotency and development.
Development. 2017 Oct 15;144(20):3646-3658. Review.
Will AJ, Cova G, Osterwalder M, Chan W-L, Wittler L, Brieske N, Heinrich V, de Villartay J-P, Vingron M, Klopocki E, Visel A, Lupiáñez DG, Mundlos S.
Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog).
Nat Genet. 2017 Oct;49(10):1539-1545. Epub 2017 Aug 28.
Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V, Schöpflin R, Kraft K, Kempfer R, Jerković I, Chan WL, Spielmann M, Timmermann B, Wittler L, Kurth I, Cambiaso P, Zuffardi O, Houge G, Lambie L, Brancati F, Pombo A, Vingron M, Spitz F, Mundlos S.
Formation of new chromatin domains determines pathogenicity of genomic duplications.
Nature 2016 Oct 13;538(7624):265-269. Epub 2016 Oct 5.
Lupiáñez DG, Spielmann M, Mundlos S.
Breaking TADs: How Alterations of Chromatin Domains Result in Disease.
Trends Genet. 2016 Apr;32(4):225-237. Epub 2016 Feb 7.
Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, Horn D, Kayserili H, Opitz JM, Laxova R, Santos-Simarro F, Gilbert-Dussardier B, Wittler L, Borschiwer M, Haas SA, Osterwalder M, Franke M, Timmermann B, Hecht J, Spielmann M, Visel A, Mundlos S.
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions.
Cell. 2015 May 21;161(5):1012-1025. Epub 2015 May 7.
Kraft K, Geuer S, Will AJ, Chan WL, Paliou C, Borschiwer M, Harabula I, Wittler L, Franke M, Ibrahim DM, Kragesteen BK, Spielmann M, Mundlos S, Lupiáñez DG, Andrey G.
Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice.
Cell Rep. 2015 Feb 4. pii: S2211-1247(15)00029-7. [Epub ahead of print]
Ibn-Salem J, Köhler S, Love MI, Chung HR, Huang N, Hurles ME, Haendel M, Washington NL, Smedley D, Mungall CJ, Lewis SE, Ott CE, Bauer S, Schofield PN, Mundlos S, Spielmann M, Robinson PN.
Deletions of chromosomal regulatory boundaries are associated with congenital disease.
Genome Biol. 2014 Sep 4;15(9):423.
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