title: Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum.
abstract: The elucidation of epigenetic alterations in the autism brain has potential to provide new insights into the molecular mechanisms underlying abnormal gene expression in this disorder. Given strong evidence that engrailed-2 (EN-2) is a developmentally expressed gene relevant to cerebellar abnormalities and autism, the epigenetic evaluation of this candidate gene was undertaken in 26 case and control post-mortem cerebellar samples. Assessments included global DNA methylation, EN-2 promoter methylation, EN-2 gene expression and EN-2 protein levels. Chromatin immunoprecipitation was used to evaluate trimethylation status of histone H3 lysine 27 (H3K27) associated with gene downregulation and histone H3 lysine 4 (H3K4) associated with gene activation. The results revealed an unusual pattern of global and EN-2 promoter region DNA hypermethylation accompanied by significant increases in EN-2 gene expression and protein levels. Consistent with EN-2 overexpression, histone H3K27 trimethylation mark in the EN-2 promoter was significantly decreased in the autism samples relative to matched controls. Supporting a link between reduced histone H3K27 trimethylation and increased EN-2 gene expression, the mean level of histone H3K4 trimethylation was elevated in the autism cerebellar samples. Together, these results suggest that the normal EN-2 downregulation that signals Purkinje cell maturation during late prenatal and early-postnatal development may not have occurred in some individuals with autism and that the postnatal persistence of EN-2 overexpression may contribute to autism cerebellar abnormalities.
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. jamesjill@uams.edu
authors: S J
authors: SJ
authors: James
authors: Svitlana
authors: S
authors: Shpyleva
authors: Stepan
authors: S
authors: Melnyk
authors: Oleksandra
authors: O
authors: Pavliv
authors: I P
authors: IP
authors: Pogribny
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult; D000099266:Engrailed 2 Protein
chemical_list: D018398:Homeodomain Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein; C524220:KDM6B protein, human