Does Aging Induce Cellular Mosaicism?

本研究项目的主要研究结果概述如下。在衰老过程中，我们发现逆转录病毒，小鼠乳腺肿瘤病毒（MMTV）的基因表达增加。这种逆转录病毒在乳腺肿瘤发生中起着至关重要的作用。MMTV基因插入突变常出现在肿瘤DNA中，提示逆转录病毒可引起衰老过程中的细胞嵌合现象.最近有报道称，Lyonized X染色体可以在衰老过程中重新激活。如果是这样的话，失活的X染色体的再激活被认为能够诱导细胞镶嵌以及逆转录病毒。我们在具有塞尔易位的小鼠中检测了这种可能性。然而，结果表明，Lyonization在衰老和癌变过程中保持稳定。因此，我们认为X染色体的再激活不能导致细胞嵌合.我们还证明了在细胞死亡和退化过程中，一些克隆比其他克隆更优先地增殖。最后，我们研究了X染色体上的调节中心在调节常染色体上的基因表达中的作用。我们的研究结果表明，即使在细胞死亡和退化过程中，X染色体的调节仍然保持紧密。总之，细胞嵌合现象是在衰老过程中通过逆转录病毒的插入突变而发生的。

The major findings made by this study project are summarized below.1. During aging, we found increases in the gene expression of a retrovirus, mouse mammary tumor virus (MMTV). This retrovirus plays a crucial role in mammary tumorigenesis. Insertional mutations of MMTV were often found in DNA from tumors, indicating that retroviruses can bring about cellular mosaicism during aging.2. It is recently reported that the Lyonized X chromosome can be reactivated during aging. If so, reactivation of the inactivated X chromosome is assumed to be able to induce cellular mosaicism as well as retroviruses. We examined this possibility in mice having Searle's translocation. The results, however, indicated the Lyonization is stably maintained both during aging and in carcinogenesis process. We, thus, concluded that reactivation of X chromosome cannot bring about cellular mosaicism.3. We also demonstrated that during the cellular death and degeneration processes, some clones proliferate more preferentially than others.4. Finally we investigated a role of the regulatory center on the X chromosome in regulating gene expression on the autosomal chromosomes. Our results indicated the regulation by the X chromosome tightly maintained even after the cellular death and degeneration process.In conclusion, the cellular mosaicism was found to occur during aging through insertional mutations by retrovirus.