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, 24 (5), 736-752.e12

Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation With Patient-Specific hiPSCs

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Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation With Patient-Specific hiPSCs

Magdalena Laugsch et al. Cell Stem Cell.

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.

Keywords: BOFS; TAD; TFAP2A; enhancer adoption; enhancer disconnection; enhancers; haploinsufficiency; long-range regulation; neural crest; structural variation.

Comment in

  • Reprogramming Nuclear Architecture: Just a TAD
    RD Acemel et al. Cell Stem Cell 24 (5), 679-681. PMID 31051129.
    In this issue of Cell Stem Cell, Laugsch et al. (2019) use direct reprogramming, epigenetics, and chromatin architecture studies to demonstrate that developmental defects …

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