The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers.
The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers.
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DOI：
10.1371/journal.pgen.1000992
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发表时间：
2010-06-17
期刊：
影响因子：
4.5
通讯作者：
Ogata T
中科院分区：
文献类型：
--
作者：
Kagami M;O'Sullivan MJ;Green AJ;Watabe Y;Arisaka O;Masawa N;Matsuoka K;Fukami M;Matsubara K;Kato F;Ferguson-Smith AC;Ogata T
人类染色体 14q32.2 包含种系来源的初级 DLK1-MEG3 基因间差异甲基化区域 (IG-DMR) 和受精后来源的次级 MEG3-DMR，以及多个印记基因。尽管之前对同时影响 DMR 和父本/母本单亲二倍体 14 样表型的微缺失和表观突变病例的研究认为，两个 DMR 对 14q32.2 印迹区域具有关键的调节功能，但单个 DMR 的确切作用仍有待阐明。我们研究了一名具有 upd(14)pat 体和胎盘表型以及仅涉及 IG-DMR 的杂合微缺失的婴儿（患者 1）和一名具有 upd(14)pat 体但无胎盘表型和仅涉及 MEG3-DMR 的杂合微缺失的新生儿（患者 2）。对这两名患者的分析得出的结果表明，IG-DMR 和 MEG3-DMR 分别作为胎盘和体内的印记控制中心，与由 IG-DMR 控制的体内甲基化模式存在分层相互作用。据我们所知，这是第一项证明二次 DMR 重要的远程印记调节功能的研究。基因组印记是导致基因以亲本特异性方式表达的过程——一些印记基因由母系遗传的染色体表达，另一些则由父系遗传的染色体表达。印记基因通常位于由根据其亲本起源差异甲基化的区域调节的簇中。人类染色体 14q32.2 印记区域包含种系来源的初级 DLK1-MEG3 基因间差异甲基化区域 (IG-DMR) 和受精后来源的次级 MEG3-DMR，以及多个印记基因。这些印记基因的剂量受到干扰，例如在患有父亲和母亲单亲二倍体 14 的患者中，会导致不同的表型。在这里，通过对具有部分或全部单亲二倍体 14 表型的微缺失患者进行分析，我们表明 IG-DMR 作为体内 MEG3-DMR 甲基化模式的上游调节因子，但在胎盘中则不然。重要的是，在体内，MEG3-DMR 充当印记控制中心。据我们所知，这是第一项证明次级 DMR 在调节多个印记基因中的重要功能的研究。因此，这些结果在阐明可调节印记的潜在表观遗传特征方面取得了重大进展。
Human chromosome 14q32.2 harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Although previous studies in cases with microdeletions and epimutations affecting both DMRs and paternal/maternal uniparental disomy 14-like phenotypes argue for a critical regulatory function of the two DMRs for the 14q32.2 imprinted region, the precise role of the individual DMR remains to be clarified. We studied an infant with upd(14)pat body and placental phenotypes and a heterozygous microdeletion involving the IG-DMR alone (patient 1) and a neonate with upd(14)pat body, but no placental phenotype and a heterozygous microdeletion involving the MEG3-DMR alone (patient 2). The results generated from the analysis of these two patients imply that the IG-DMR and the MEG3-DMR function as imprinting control centers in the placenta and the body, respectively, with a hierarchical interaction for the methylation pattern in the body governed by the IG-DMR. To our knowledge, this is the first study demonstrating an essential long-range imprinting regulatory function for the secondary DMR. Genomic imprinting is a process causing genes to be expressed in a parent-of-origin specific manner—some imprinted genes are expressed from maternally inherited chromosomes and others from paternally inherited chromosomes. Imprinted genes are often located in clusters regulated by regions that are differentially methylated according to their parental origin. The human chromosome 14q32.2 imprinted region harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Perturbed dosage of these imprinted genes, for example in patients with paternal and maternal uniparental disomy 14, causes distinct phenotypes. Here, through analysis of patients with microdeletions recapitulating some or all of the uniparental disomy 14 phenotypes, we show that the IG-DMR acts as an upstream regulator for the methylation pattern of the MEG3-DMR in the body but not in the placenta. Importantly, in the body, the MEG3-DMR functions as an imprinting control center. To our knowledge, this is the first study demonstrating an essential function for the secondary DMR in the regulation of multiple imprinted genes. Thus, the results provide a significant advance in the clarification of underlying epigenetic features that can act to regulate imprinting.
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