TY - JOUR

T1 - Regulatory variants of FOXG1 in the context of its topological domain organisation

AU - Mehrjouy, Mana M

AU - Fonseca, Ana Carolina S

AU - Ehmke, Nadja

AU - Paskulin, Giorgio

AU - Novelli, Antonio

AU - Benedicenti, Francesco

AU - Mencarelli, Maria Antonietta

AU - Renieri, Alessandra

AU - Busa, Tiffany

AU - Missirian, Chantal

AU - Hansen, Claus

AU - Abe, Kikue Terada

AU - Speck-Martins, Carlos Eduardo

AU - Vianna-Morgante, Angela M

AU - Bak, Mads

AU - Tommerup, Niels

PY - 2018

Y1 - 2018

N2 - FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.

AB - FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.

U2 - 10.1038/s41431-017-0011-4

DO - 10.1038/s41431-017-0011-4

M3 - Journal article

C2 - 29289958

VL - 26

SP - 186

EP - 196

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 2

ER -