Identification of New Human Imprinted Genes: A Novel Approach

“印记”基因对人类正常生长和发育至关重要。我们几乎所有的基因都是成对出现的，每个基因对的一个拷贝继承自我们的母亲（母系），另一个来自我们的父亲（父系）。对于我们绝大多数的基因对来说，从每个父母那里继承的拷贝是平等表达的。然而，印记基因以来源特异性的方式表达。也就是说，基因是从母本或父本拷贝转录（读取）的，而不是两者，并且这些基因的表达在特定组织中可能不同。实现这种特殊类型的转录的机制被称为表观遗传。表观遗传标记，如DNA甲基化，通过使其无法进入细胞中的转录机制，基本上使基因沉默。印记基因通常在成对的两个亲本基因上具有相反的表观遗传标记，一个甲基化（沉默），另一个未甲基化（转录）。 这就是所谓的差异DNA甲基化。 在每个人类细胞中大约25，000个基因中，迄今为止只发现了62个印记基因。我们的假设是，有更多的人类印记基因比62已经确定。我们已经开发出一种新的方法来直接识别人类中的新印记基因。这种方法利用了罕见的人类组织，这些组织仅携带来自一个亲本（母亲或父亲）的部分或全部基因;这被称为单亲（一个亲本）二体性（两个拷贝）。我们已经证明，比较DNA甲基化在这些单亲组织正常的双亲组织，使我们能够确定差异DNA甲基化标记的印记基因的特征。使用这种方法和最先进的新技术，我们将捕获新的候选印记基因。我们希望这些实验将增加识别的人类印记基因的数量，并最终增强我们对它们的调节功能如何指导人类正常发育的理解。

"Imprinted" genes are critical for normal human growth and development. Almost all of our genes occur in pairs, with one copy of each gene pair inherited from our mother (maternal) and the other from our father (paternal). For the vast majority of our gene pairs, the copy inherited from each parent is expressed equally. However, imprinted genes are expressed in a parent of origin-specific manner. That is, the genes are transcribed (read) from either the maternal or paternal copy, not both, and the expression of these genes may differ in specific tissues. The mechanism by which this special type of transcription is achieved is termed epigenetic. Epigenetic marks, such as DNA methylation, essentially silence the gene by making it inaccessible to the transcription machinery in the cell. Imprinted genes typically have opposite epigenetic marks on the two parental genes in the pair, one methylated (silenced) and the other not methylated (transcribed). This is called differential DNA methylation. Of the approximately 25,000 genes in every human cell, there are only 62 imprinted genes identified to date. Our hypothesis is that there are more human imprinted genes than the 62 that have already been identified. We have developed a novel approach to directly identify new imprinted genes in humans. This approach utilizes rare human tissues that carry some or all of their genes from only one parent, either mother or father; this is termed uniparental (one parent) disomy (two copies). We have demonstrated that comparing DNA methylation in these uniparental tissues to normal biparental tissues allows us to identify differential DNA methylation marks that are characteristic of imprinted genes. Using this approach and new state-of-the-art technology, we will capture new candidate imprinted genes. We expect that these experiments will increase the number of identified human imprinted genes and will ultimately enhance our understanding of how their regulation functions to guide normal human development.