title: Methylation and expression analyses of Pallister-Killian syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p.
abstract: To ascertain the epigenomic features, i.e., the methylation, non-coding RNA, and gene expression patterns, associated with gain of i(12p) in Pallister-Killian syndrome (PKS), we investigated single cell clones, harboring either disomy 12 or tetrasomy 12p, from a patient with PKS. The i(12p)-positive cells displayed a characteristic expression and methylation signature. Of all the genes on 12p, 13% were overexpressed, including the ATN1, COPS7A, and NECAP1 genes in 12p13.31, a region previously implicated in PKS. However, the median expression fold change (1.3) on 12p was lower than expected by tetrasomy 12p. Thus, partial dosage compensation occurs in cells with i(12p). The majority (89%) of the significantly deregulated genes were not situated on 12p, indicating that global perturbation of gene expression is a key pathogenetic event in PKS. Three genes-ATP6V1G1 in 9q32, GMPS in 3q25.31, and TBX5 in 12q24.21-exhibited concomitant hypermethylation and decreased expression. The i(12p)-positive cells displayed global hypomethylation of gene-poor regions on 12p, a footprint previously associated with constitutional and acquired gains of whole chromosomes as well as with X-chromosome inactivation in females. We hypothesize that this non-genic hypomethylation is associated with chromatin processing that facilitates cellular adaptation to excess genetic material.
authors.affiliation: a Division of Molecular Hematology, Department of Laboratory Medicine , Lund University , Lund , Sweden.|b Division of Clinical Genetics, Department of Laboratory Medicine , Lund University , Lund , Sweden.
authors.forename: Josef
authors.initials: J
authors.lastname: Davidsson
authors.affiliation: b Division of Clinical Genetics, Department of Laboratory Medicine , Lund University , Lund , Sweden.|c Department of Clinical Genetics, Office for Medical Services , Division of Laboratory Medicine , Lund , Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D002843:Chromatin / Q000235:genetics; D025063:Chromosome Disorders / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D059010:Single-Cell Analysis; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D058670:Tetrasomy / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D002843:Chromatin; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C000594810:ATP6V1G1 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: Dosage compensation; Pallister-Killian; expression; methylation