Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain.
Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X-chromosome determines these features of KS are poorly understood, skewed X-chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes. We assessed genomic, methylomic and transcriptomic variation in matched prefrontal cortex and cerebellum samples identifying an individual with a 47,XXY karyotype who was comorbid for schizophrenia and had a notably reduced cerebellum mass compared with other individuals in the study (n = 49). We examined methylomic and transcriptomic differences in this individual relative to female and male samples with 46,XX or 46,XY karyotypes, respectively, and identified numerous locus-specific differences in DNA methylation and gene expression, with many differences being autosomal and tissue-specific. Furthermore, global DNA methylation, assessed via the interrogation of LINE-1 and Alu repetitive elements, was significantly altered in the 47,XXY patient in a tissue-specific manner with extreme hypomethylation detected in the prefrontal cortex and extreme hypermethylation in the cerebellum. This study provides the first detailed molecular characterization of the prefrontal cortex and cerebellum from an individual with a 47,XXY karyotype, identifying widespread tissue-specific epigenomic and transcriptomic alterations in the brain.
University of Exeter Medical School; Exeter University; Exeter, UK.
Joana
J
Viana
Institute of Psychiatry; King's College London; London, UK; Garvan Institute of Medical Research; Sydney, NSW Australia.
Ruth
R
Pidsley
Institute of Psychiatry; King's College London; London, UK.
Claire
C
Troakes
Institute of Psychiatry; King's College London; London, UK.
Helen
H
Spiers
Institute of Psychiatry; King's College London; London, UK.
Chloe Cy
CC
Wong
Institute of Psychiatry; King's College London; London, UK.
Safa
S
Al-Sarraj
Institute of Psychiatry; King's College London; London, UK.
Ian
I
Craig
Institute of Psychiatry; King's College London; London, UK.
Leonard
L
Schalkwyk
University of Exeter Medical School; Exeter University; Exeter, UK; Institute of Psychiatry; King's College London; London, UK.
Jonathan
J
Mill
D020087:Alu Elements; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007713:Klinefelter Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications; D059467:Transcriptome
47,XXY; DNA methylation; Klinefelter syndrome; cerebellum; gene expression; prefrontal cortex