Welcome back RSG friends! Christmas is close but we did not forget about you. As a special gift this month we revise three papers in the field of epigenetics. No worries, it’s not about the usual and popular chromatin modifications that we are going to discuss. In fact we will discuss about modifications that happen in the DNA and RNA and their possible implication in gene regulation and human disease/infections. Finally we also discuss about a nice database that annotate all the possible DNA modifications found until now reporting the nomenclature and the sequencing methods to study them. We hope you appreciate this topic, have fun and keep in touch. See you next year! Yours:
RGS Germany (ISCB Student Council) – Tommaso Andreani, Ilkay Başak Uysal, Neetika Nath, Nikos Papadopoulos, Yvonne Gladbach
Epitranscriptomics of cancer
The comprehensive RNA code remains not fully understood due to its complexity and difficulty of having just one snapshot of expression in one moment of sequencing. RNA-modifications and RNA-binding proteins play important roles in diverse biological processes and in diseases. Further, distinct post-transcriptional RNA modifications might be key players in transgenerational epigenetic inheritance and need therefore further investigation. Epitranscriptomics provides new insights into how reversibly modified RNA bases control the fate of mRNA.
Some modifications are able to promote, while others decrease major cancer competences as growth and invasiveness while opening new avenues and potential therapeutic applications to treat cancer. Linking RNA-modifications and cancer is essentially based on systematically addressing the “pro-cancer”, “anti-cancer” and mixed effects.
One popular modification is the mRNA 5’ cap methylation of the exocyclic nitrogen of adenosine (m6A). This modification has been identified in rRNA, tRNA, snRNA, miRNA, and lncRNA. m6A dynamics comprises “writers”, “readers” and “erasers”. “Writers” are enzymes that are part of the methyltransferase complex that introduces m6A. m6A-modified mRNAs sites can be recognized from m6A-binding proteins – (or “readers”) and removed by another class of protein called “erasers”. The latter are involved in the removal of the modification in order to replace the unmodified base on the RNA. These properties highlight a possible signature for specific types of cancer due to the removal or introduction of modification caused by misbalanced expression.
Tusup, Marina, et al. “Epitranscriptomics of cancer.” World J. Clin. Oncol. 9.3 (2018): 42-55.
Making the mark: the role of adenosine modifications in the life cycle of RNA viruses
It has recently become clear that epigenetic modifications are not limited to DNA. Over 100 RNA modifications have been identified, and while most don’t have a known role it is clear that they impact multiple facets of RNA life, including, but not limited to, the translation efficiency and stability of mRNA. In this article the authors consolidate the effects of four adenosine modifications on the life cycle of certain RNA viruses. In the case of HIV, a particular adenosine methylation (m6A) promotes HIV replication. While the biological mechanism is not yet elucidated, erasing m6A clearly inhibits HIV growth, while depleting m6A erasers leads to increased infection. Other viruses employ methyltransferases to mask their RNA from triggering an antiviral response from the immune system, or use epitranscriptomic marks to coordinate their replication with other cell activities. The search for mechanistic insight hinges critically on the analysis of the data, where standardized, rigorous bioinformatics methods are missing.
Gonzales-van Horn, Sarah R., and Peter Sarnow. “Making the mark: The role of adenosine modifications in the life cycle of RNA viruses.” Cell host & microbe 21.6 (2017): 661-669.
DNAmod: the DNA modification database
One of the best known and more studied DNA modification is the methylation at the carbon five of the cytosine 5mC. It is considered the fifth DNA base and is involved in several biological processes from gene regulation to mobile DNA elements silencing. Given the importance of this modification as a stable epigenetic mark, other less studied DNA modifications might play an important role for organisms physiology. To circumvent this, the lab of Michael Hoffman has implemented a database: “DNAmod”.
The database annotates the chemical properties and structures of all curated modified DNA bases, and a much larger list of candidate chemical entities. It includes manual annotations of available sequencing methods, descriptions of their occurrence in nature, and provides existing and suggested nomenclature. Finally, it enables researchers to rapidly review previous work, select mapping techniques, and track recent developments concerning modified bases of interest. Wonderful resource/tool for the epigenetics community!!