Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes.
Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes.
复制标题
DOI：
10.1136/jmedgenet-2013-102116
复制
发表时间：
2014-04
影响因子：
4
通讯作者：
Mackay DJ
中科院分区：
文献类型：
--
作者：
Docherty LE;Rezwan FI;Poole RL;Jagoe H;Lake H;Lockett GA;Arshad H;Wilson DI;Holloway JW;Temple IK;Mackay DJ
基因组印记是指基因表达潜能的等位基因限制，依赖于亲本来源，由表观遗传机制维持，包括亲本来源特异性DNA甲基化。在大约70个已知的印记基因中，有一些会导致影响生长、代谢和癌症易感性的疾病。一些印迹障碍患者在整个基因组中有几个印迹位点（HIL）的低甲基化，并可能具有严重的临床特征。在这里，我们在HIL患者中使用阵列分析来确定整个基因组中异常甲基化的模式。我们开发了一种新的信息管道，能够进行小样本量分析，并使用Illumina Infinium Human Methylation 450 BeadChip阵列对10名具有两种临床表现（Beckwith-Wiedemann综合征和新生儿糖尿病）的HIL患者进行了分析，以确定候选印迹区域。我们使用稳健的统计标准来量化DNA甲基化。我们在已知的印迹位点检测到低甲基化，以及25个进一步的候选印迹区域（9个在患者组之间共享），包括唐氏综合征关键区域（WRB）和另一个先前与双相情感障碍（PPIEL）相关的区域。三个候选区域（NHP 2L 1，WRB和PPIEL）的靶向分析显示等位基因表达，甲基化模式与等位基因母体甲基化一致，并且在另一组HIL患者中频繁发生低甲基化，包括6例Silver-Russell综合征表现和1例假性甲状旁腺功能减退1B。这项研究确定了新的候选印记基因，揭示了临床上不同患者之间显着的表观遗传收敛，并强调了表观基因组分析的潜力，以扩大我们对正常甲基化及其在人类疾病中的破坏的理解。
Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome. We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith–Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation. We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver–Russell syndrome presentations and one with pseudohypoparathyroidism 1B. This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.
登录
查看更多内容
影响因子：
3.7
作者：
Boks MP;Derks EM;Weisenberger DJ;Strengman E;Janson E;Sommer IE;Kahn RS;Ophoff RA
通讯作者：
Ophoff RA
影响因子：
3.5
作者：
Dempster EL;Pidsley R;Schalkwyk LC;Owens S;Georgiades A;Kane F;Kalidindi S;Picchioni M;Kravariti E;Toulopoulou T;Murray RM;Mill J
通讯作者：
Mill J
通过RNA-Seq对印迹基因表达的批判性评估：一种新的观点。
影响因子：
4.5
作者：
DeVeale B;van der Kooy D;Babak T
通讯作者：
Babak T
影响因子：
3.8
作者：
Dedeurwaerder, Sarah;Defrance, Matthieu;Fuks, Francois
通讯作者：
Fuks, Francois
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y