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目的探讨雌激素受体2基因(Estrogen Receptor beta,ESR2)的表观遗传修饰作用与孤独症发病的关联性,为孤独症的病因学研究提供依据。方法收集哈尔滨医科大学儿童发育行为研究中心的孤独症男性患儿54例,并按年龄-性别匹配原则随机收集正常对照男性儿童54名,运用亚硫酸盐测序法(Bisulfite Sequencing PCR,BSP)检测外周血细胞ESR2基因5’近端调控区的DNA甲基化。通过Mann-Whitney U检验比较病例组和对照组的DNA甲基化水平。结果ESR2基因5’近端调控区的整体甲基化水平在孤独症组和对照组间的差异无统计学意义(P>0.05),但启动子区甲基化岛(Prom CGI)所包含的15个Cp G位点中,有7个位点(Cp G 5,6,8,9,10,11和12)的甲基化水平在孤独症组明显升高(P值均<0.05),部分位点存在于转录因子结合位点的保守序列中,包括USF2,ZBTB33,REL,ESR2和TFEC。此外,外显子区甲基化岛(Exon CGI)包含26个Cp G位点,其中Cp G41位点的甲基化水平在孤独症组(31.30±2.74)%高于对照组(24.07±2.59)%(P<0.05)。结论 ESR2基因5’近端调控区的表观遗传修饰与孤独症的发病有明显关联。
Objective To investigate the relationship between epigenetic modification of estrogen receptor 2 (ESR2) and the pathogenesis of autism and to provide basis for the etiological study of autism. Methods Fifty-four male patients with autism were collected from Children’s Developmental Behavior Research Center of Harbin Medical University. Fifty-four normal control male children were collected according to age-sex matching principle. Bisulfite Sequencing PCR (BSP) DNA methylation in 5 ’proximal regulatory region of ESR2 gene in blood cells. Mann-Whitney U test was used to compare DNA methylation levels between case and control groups. Results The overall methylation level of the 5 ’regulatory region of ESR2 gene was not significantly different between autism group and control group (P> 0.05). However, the promoter region methylation island (Prom CGI) The methylation level of 7 of 15 CpG sites (CpGs 5, 6, 8, 9, 10, 11 and 12) was significantly higher in autism group (all P <0.05) Partial loci exist in conserved sequences of transcription factor binding sites, including USF2, ZBTB33, REL, ESR2 and TFEC. In addition, Exon CGI contained 26 CpG sites, of which the CpG41 methylation level was higher in autism group (31.30 ± 2.74)% than in control group (24.07 ± 2.59) )% (P <0.05). Conclusion The epigenetic modification of 5 ’proximal regulatory region of ESR2 gene is significantly associated with the onset of autism.