The function of the RNA methylome in animals

点击翻译按钮获取中文摘要

Our DNA contains the core genetic information that is inherited by our children. This genetic information programs how and when genes will be expressed within the diverse number of cells of an organism. Epigenetic mechanisms such as chromatin and DNA modifications give rise to heritable gene expression changes without affecting the DNA code. Research in epigenetics led to the discoveries of novel gene regulatory mechanisms with heritable features. A similar paradigm has now emerged with RNA. RNA carries the message encoded in the DNA. Yet this message itself can also be altered by chemical modifications. There are currently more than 150 diverse modifications found on RNA and a greater number of proteins are required for their biogenesis and recognition. Recent discoveries have shown that RNA modifications can be dynamically regulated and they have been implicated in embryonic development, longevity, neurological diseases and cancers in humans and in animal models.The heritable nature of epigenetic mechanisms requires gene expression changes within the germ cells, which give rise to the offspring. Germline development, germ cell proliferation and identity are essential for the survival of organisms. Epigenetic mechanisms play key roles in genome defence by targeting foreign elements and they also prevent somatic gene expression in the germ cells. Still, in some animals, it is possible to reprogram the epigenetic pathways to establish heritable gene expression changes that can last many generations.The biological role of most RNA modifications remains unclear in multicellular organisms and their role in heritable gene expression regulation is not explored. Research using the nematode Caenorhabditis elegans as an animal model made pioneering contributions to the discovery and understanding of epigenetic gene regulatory pathways in animal germlines. Up until recently, the RNA modification landscape of C. elegans was not know. In order to establish C. elegans as a model system to study the role of RNA modifications, I developed mass spectrometry methods that enable the identification and quantification of modified RNAs. Using these methods, I showed that several RNA modifications found in C. elegans show changes upon stress such as dietary restriction or high temperatures. In some instances, these changes in RNA modifications can be reversed.My research aims to uncover the role of a specific group of RNA modifications that contain a methyl group. By understanding how RNA methylations contribute to gene expression changes in germ cells, I aim to discover their epigenetic functions. Using a combination of biochemical and genetic methods, I will(i) develop an enzyme specific sequencing method for methylated RNAs(ii) study the role of RNA methylations in animal germ cells(iii) investigate how RNA methylome itself is regulated by dietary metabolismThis research is important because, first the proposed sequencing method will benefit a large research community and enable the profiling of RNA methylations in multicellular organisms. Second, understanding the role of RNA modifications in germ cells will reveal their role in cell proliferation and differentiation that will benefit research in human diseases such as cancer and fertility. And finally, my research has the potential to pioneer a new research direction on how our diet can affect gene expression through RNA modifications.