Dataset related to article "Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism"
- 1. 1Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, 41013 Seville, Spain
- 2. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium
- 3. Department of Human Genetics, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium
- 4. NET Service and Endocrine Oncology Bioinformatics Lab, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, 5265601 Ramat Gan, Israel
- 5. Endocrinology - Department of Clinical and Molecular Medicine. Sant'Andrea Hospital - Sapienza University of Rome, 00189 Rome, Italy AND Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 20892 Bethesda, Maryland, USA
- 6. a)Laboratory of Cellular and Molecular Endocrinology and b)Laboratory of Pharmacology and Brain Pathology, Humanitas Research Hospital – IRCCS, 20089 Rozzano (Mi) – Italy
- 7. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 20892 Bethesda, Maryland, USA
- 8. Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium
- 9. Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, 41013 Seville, Spain
- 10. Laboratory of Cellular and Molecular Endocrinology , Humanitas Research Hospital – IRCCS, 20089 Rozzano (Mi) – Italy
- 11. IRCCS Humanitas Research Hospital, via Manzoni 56,20089 Rozzano (Mi) - Italy AND Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele – Milan, Italy
- 12. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 20892 Bethesda, Maryland, USA AND Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, N. Plastira 100, Vassilika Vouton GR – 700 13, Heraklion, Crete, Greece AND Research Institute, ELPEN, SA, Athens, Greece
- 13. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 20892 Bethesda, Maryland, USA AND Laboratory of Cellular and Molecular Endocrinology and Laboratory of Pharmacology and Brain Pathology, Humanitas Research Hospital – IRCCS, 20089 Rozzano (Mi) – Italy
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This record contains raw data related to article “Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism"
X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)- secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus.We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG.We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101- enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
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