Identification of New Human Imprinted Genes: A Novel Approach

“印记”基因对人类的正常生长发育至关重要。我们几乎所有的基因都是成对出现的，每对基因的一个拷贝来自我们的母亲(母亲)，另一个来自我们的父亲(父亲)。对于我们的绝大多数基因对来说，从每个父母那里继承的拷贝是平等表达的。然而，印记基因是以特定来源的亲本方式表达的。也就是说，这些基因是从母体或父体中转录(读取)的，而不是两者都有，而且这些基因在特定组织中的表达可能不同。实现这种特殊类型转录的机制被称为表观遗传。表观遗传标记，如DNA甲基化，本质上使基因沉默，使其无法进入细胞中的转录机器。印记基因通常在两个亲本基因上有相反的表观遗传标记，一个甲基化(沉默)，另一个没有甲基化(转录)。这被称为差异DNA甲基化。 在每个人类细胞中的大约25,000个基因中，到目前为止只有62个印记基因被识别出来。我们的假设是，人类印记基因的数量比已经确定的62个基因要多。我们开发了一种新的方法来直接在人类中识别新的印记基因。这种方法利用了罕见的人类组织，这些组织只携带来自父母之一的部分或全部基因；这被称为单亲(单亲)二体(两个副本)。我们已经证明，将这些单亲组织和正常双亲组织中的DNA甲基化进行比较，可以识别印记基因特有的差异DNA甲基化标记。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。我们预计，这些实验将增加已识别的人类印记基因的数量，并最终增强我们对它们如何调节功能以指导正常人类发育的理解。

"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.