Which are the rules dictating the responsiveness between genes and enhancers?
Speaker: Álvaro Rada Iglesias
Institute of Biomedicine & Biotechnology of Cantabria (IBBTEC) (IBBTEC) [Santander]
Host: Mercedes Dosil
Salón de actos del Centro de Investigación del Cáncer
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 (hNCC). 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 or ectopic gains in gene expression. Instead, the inversion disconnects one TFAP2A allele from its cognate enhancers, leading to monoallelic and haploinsufficient TFAP2A expression in patient hNCC. Therefore, our work highlights the power of hiPSCs differentiation to unveil the pathological mechanisms whereby structural variants can cause congenital abnormalities. Furthermore, our work shows that placing enhancer and genes within the same TAD is not sufficient for enhancer adoption to take place, suggesting that additional and largely unknown regulatory layers are required for efficient enhancer-gene communication. Lastly, we will present preliminary data illustrating how we are trying to dissect the regulatory logic governing the compatibility and responsiveness between genes and enhancers, which we believe, includes genetic, epigenetic and structural factors.