Universität zu Köln

Laugsch, Magdalena, Bartusel, Michaela, Rehimi, Rizwan, Alirzayeva, Hafiza, Karaolidou, Agathi, Crispatzu, Giuliano, Zentis, Peter, Nikolic, Milos ORCID: 0000-0003-0029-7601, Bleckwehl, Tore, Kolovos, Petros ORCID: 0000-0002-0787-6158, van Ijcken, Wilfred F. J., Saric, Tomo, Koehler, Katrin, Frommolt, Peter ORCID: 0000-0002-1966-8014, Lachlan, Katherine, Baptista, Julia and Rada-Iglesias, Alvaro (2019). Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs. Cell Stem Cell, 24 (5). S. 736 - 765. CAMBRIDGE: CELL PRESS. ISSN 1875-9777

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Abstract

The pathological consequences of structural variants disrupting 3D genome organization can be difficult to elucidate in vivo due to differences in gene dosage sensitivity between mice and humans. This is illustrated by branchiooculofacial syndrome (BOFS), a rare congenital disorder caused by heterozygous mutations within TFAP2A, a neural crest regulator for which humans, but not mice, are haploinsufficient. Here, we present a BOFS patient carrying a heterozygous inversion with one breakpoint located within a topologically associating domain (TAD) containing enhancers essential for TFAP2A expression in human neural crest cells (hNCCs). Using patient-specific hiPSCs, we show that, although the inversion shuffles the TFAP2A hNCC enhancers with novel genes within the same TAD, this does not result in enhancer adoption. Instead, the inversion disconnects one TFAP2A allele from its cognate enhancers, leading to monoallelic and haploinsufficient TFAP2A expression in patient hNCCs. Our work illustrates the power of hiPSC differentiation to unveil long-range pathomechanisms.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Laugsch, Magdalena UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartusel, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehimi, Rizwan UNSPECIFIED UNSPECIFIED UNSPECIFIED Alirzayeva, Hafiza UNSPECIFIED UNSPECIFIED UNSPECIFIED Karaolidou, Agathi UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, Giuliano UNSPECIFIED UNSPECIFIED UNSPECIFIED Zentis, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolic, Milos UNSPECIFIED orcid.org/0000-0003-0029-7601 UNSPECIFIED Bleckwehl, Tore UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolovos, Petros UNSPECIFIED orcid.org/0000-0002-0787-6158 UNSPECIFIED van Ijcken, Wilfred F. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saric, Tomo UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommolt, Peter UNSPECIFIED orcid.org/0000-0002-1966-8014 UNSPECIFIED Lachlan, Katherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Baptista, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Rada-Iglesias, Alvaro UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-148618
DOI:	10.1016/j.stem.2019.03.004
Journal or Publication Title:	Cell Stem Cell
Volume:	24
Number:	5
Page Range:	S. 736 - 765
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1875-9777
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-EXPRESSION; TFAP2A MUTATIONS; CHROMATIN; PLATFORM; BINDING; QUANTIFICATION; REORGANIZATION; IDENTIFICATION; TRANSCRIPTS; DISRUPTION Multiple languages Cell & Tissue Engineering; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14861