DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians.
DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians.
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DOI：
10.1111/epi.14058
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发表时间：
2018-05
期刊：
影响因子：
5.6
通讯作者：
Greenberg DA
中科院分区：
文献类型：
--
作者：
Pathak S;Miller J;Morris EC;Stewart WCL;Greenberg DA
青少年肌阵挛性癫痫（JME）是一种常见的遗传性全身性癫痫（GGE）综合征。多个连锁和关联研究发现BRD2影响JME的表达。我们的鼠模型进一步证实了BRD2-JME的联系：Brd2单倍不足产生了代表JME临床标志的特征。无论是我们，还是几项大规模的JME研究，都没有发现JME相关的BRD2编码突变。因此，我们研究了BRD2的非编码区，寻找BRD2的JME影响的起源。BRD2的启动子含有一个JME相关的SNP（rs3918149）和一个CpG（C-磷酸-G二核苷酸）岛（CpG 76），使其成为JME相关表观遗传变异的潜在“热点”。甲基化启动子CpG位点导致基因沉默，通常导致基因表达减少。我们在三个不同的亚组中测试了CpG 76处DNA甲基化的差异：1）JME患者与其未受影响的家庭成员，2）JME与其他形式的GGE患者，以及3）高加索人与非高加索人JME患者。我们使用DNA焦磷酸测序分析了10个BRD2启动子CpG位点在淋巴母细胞样细胞中的甲基化状态，这些细胞来自高加索人和非高加索人来源的JME患者、未受影响的家庭成员以及非JME GGE患者。我们还通过标准方法测量了JME家族的整体甲基化水平和DNA甲基转移酶1（DNMT1）转录本表达。与未受影响的家族成员相比，JME患者中CpG76高度甲基化。在非JME GGE家族中，我们发现启动子甲基化与癫痫之间没有关系。在非高加索人JME家族中，启动子甲基化大多与癫痫无关。这使得BRD 2启动子成为JME特异性、种族特异性、差异甲基化区域。总体甲基化在各组中是恒定的。JME中BRD2启动子甲基化，以及未受影响的亲属、非JME GGE患者和非高加索人JME中甲基化的缺乏，表明甲基化特异性是JME风险中可能的癫痫发作易感性基序，并提示JME治疗靶向BRD2。
Juvenile Myoclonic Epilepsy (JME) is a common adolescent-onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that BRD2 influences the expression of JME. The BRD2-JME connection is further corroborated by our murine model: Brd2 haplo-insufficiency produces characteristics that typify the clinical hallmarks of JME. Neither we, nor several large-scale studies of JME, found JME-related BRD2 coding mutations. Therefore, we investigated non-coding BRD2 regions, seeking the origin of BRD2’s JME influence. BRD2’s promoter harbors a JME-associated SNP (rs3918149) and a CpG (C-phosphate-G dinucleotides) island (CpG76), making it a potential “hotspot” for JME-associated epigenetic variants. Methylating promoter CpG sites causes gene silencing, often resulting in reduced gene expression. We tested for differences in DNA methylation at CpG76 in three different subgroups: 1) JME patients vs. their unaffected family members, 2) JME vs. patients with other forms of GGE, and 3) Caucasian vs. non-Caucasian JME patients. We used DNA pyrosequencing to analyze the methylation status of 10 BRD2 promoter CpG sites in lymphoblastoid cells from JME patients of Caucasian and non-Caucasian origin, unaffected family members, and also non-JME GGE patients. We also measured global methylation levels and DNA methyl transferase 1 (DNMT1) transcript expression in JME families by standard methods. CpG76 is highly methylated in JME patients compared to unaffected family members. In families with non-JME GGE, we found no relationship between promoter methylation and epilepsy. In non-Caucasian JME families, promoter methylation was mostly not associated with epilepsy. This makes the BRD2 promoter a JME-specific, ethnicity-specific, differentially methylated region. Global methylation was constant across groups. BRD2 promoter methylation in JME, and the lack of methylation in unaffected relatives, in non-JME GGE patients, and in non-Caucasian JME, demonstrates that methylation specificity is a possible seizure susceptibility motif in JME risk and suggests JME therapeutics targeting BRD2.
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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
影响因子：
7.7
作者：
Gutierrez-Arcelus M;Lappalainen T;Montgomery SB;Buil A;Ongen H;Yurovsky A;Bryois J;Giger T;Romano L;Planchon A;Falconnet E;Bielser D;Gagnebin M;Padioleau I;Borel C;Letourneau A;Makrythanasis P;Guipponi M;Gehrig C;Antonarakis SE;Dermitzakis ET
通讯作者：
Dermitzakis ET
DOI：
10.1016/j.bbagrm.2009.03.005
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Gyuris A;Donovan DJ;Seymour KA;Lovasco LA;Smilowitz NR;Halperin AL;Klysik JE;Freiman RN
通讯作者：
Freiman RN
影响因子：
5.6
作者：
Greenberg DA;Stewart WC
通讯作者：
Stewart WC
影响因子：
25
作者：
Hannon E;Spiers H;Viana J;Pidsley R;Burrage J;Murphy TM;Troakes C;Turecki G;O'Donovan MC;Schalkwyk LC;Bray NJ;Mill J
通讯作者：
Mill J