Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs
Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs
复制标题
DOI：
10.1016/j.stem.2019.03.004
复制
发表时间：
2019-05-02
期刊：
影响因子：
23.9
通讯作者：
Rada-Iglesias, Alvaro
中科院分区：
文献类型：
--
作者：
Laugsch, Magdalena;Bartusel, Michaela;Rada-Iglesias, Alvaro
由于小鼠和人类之间基因剂量敏感性的差异，结构变异破坏3D基因组组织的病理后果很难在体内阐明。这可以从面部分枝综合征（BOFS）中得到证明，这是一种罕见的先天性疾病，由TFAP2A的杂合突变引起，TFAP2A是一种神经嵴调节因子，人类（而不是小鼠）缺乏单倍体。在这里，我们提出了一个携带杂合反转的BOFS患者，其断点位于人类神经嵴细胞（hncc）中含有TFAP2A表达必需增强子的拓扑相关结构域（TAD）内。使用患者特异性hipsc，我们发现，尽管倒置会将TFAP2A hNCC增强子与同一TAD内的新基因进行洗牌，但这不会导致增强子的采用。相反，倒置将一个TFAP2A等位基因与其同源增强子断开，导致患者hncc中单等位基因和单倍体TFAP2A表达不足。我们的工作说明了hiPSC分化揭示长期病理机制的力量。
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.