GSE193113
Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]
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 the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, 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. Then, we showed that the duplications in multiple patients 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. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary. Overall design: Human 4C-seq profiles derived from 6 blood-derived cells of individuals with X-linked acrogigantism and 3 healthy independent controls.