Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C.
BACKGROUND
A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.


RESULTS
Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.


CONCLUSIONS
We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.
Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
Daria
D
Grafodatskaya
Barian H Y
BH
Chung
Darci T
DT
Butcher
Andrei L
AL
Turinsky
Sarah J
SJ
Goodman
Sana
S
Choufani
Yi-An
YA
Chen
Youliang
Y
Lou
Chunhua
C
Zhao
Rageen
R
Rajendram
Fatima E
FE
Abidi
Cindy
C
Skinner
James
J
Stavropoulos
Carolyn A
CA
Bondy
Jill
J
Hamilton
Shoshana
S
Wodak
Stephen W
SW
Scherer
Charles E
CE
Schwartz
Rosanna
R
Weksberg
D001772:Blood Cell Count; D001921:Brain / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000097:blood / Q000235:genetics; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000097:blood / Q000235:genetics; D005260:Female; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D063146:Polycomb-Group Proteins / Q000097:blood / Q000235:genetics; D011401:Promoter Regions, Genetic; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000097:blood / Q000235:genetics
C491778:CACYBP protein, human; D002135:Calcium-Binding Proteins; D044783:F-Box Proteins; C521741:FBXL5 protein, human; D006657:Histones; D063146:Polycomb-Group Proteins; C570430:Scmh1 protein, mouse; D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases