RNA editing is an important post-transcriptional mechanism occurring in a wide range of organisms, which alters the primary RNA sequence through the insertion/deletion or modification of specific nucleotides, thus adding functional variation. In human, the most common type of RNA editing is mediated by the ADAR family of enzymes, and converts Adenosine (A) to Inosine (I, interpreted as Guanosine by the cellular machineries) within dsRNAs (coding and noncoding). Recently, it has been shown that the A-to-I RNA editing frequency is massively increased in human compared to mouse. Fascinatingly, in humans, most A-to-I RNA editing events (>=90%) occur in Alu containing transcripts that are preferentially localized in gene-rich regions. A-to-I RNA editing within Alu elements, ncRNAs (long ncRNA, miRNAs) and mRNAs may contribute to the human RNA landscape with essential functions in normal as well as in pathological conditions. Peripheral blood monocytes can differentiate to populations with opposite functions in modulating the immune response in infectious diseases as well in cancer.
In this project, we will explore the role played by the ADAR enzymes in the myeloid cell differentiation, with particular emphasis in some of the substrates we have identified in our previous work.
There are two main questions that this project is aimed to contribute to answer:
1) the balance between proliferation and differentiation is the key question of cancer progression. In particular, in myeloid cells, leukemiogenesis can be regarded as a block of cell differentiation leading to an uncontrolled growth with devastating consequences. It is therefore crucial to understand what is the turning point of the process.
In this context, the ADARs can play some role as we have recently contributed to shown. Unfortunately, very little is known about these enzymes and their role in the process of differentiation. From this point of view, the project is highly innovative and the first part of the results have been published in a prestigious journal (Ref.16).
2) the second part of the project is aimed to understand the functional role of some of the targets which are edited during the differentiation process as well as in monocytes, the final step of myeloid cell differentiation. However, circulating monocytes can migrate in tissues and further differentiate to macrophages with specific role in the immune defence. What is the role of the ADARs in this process is completely unknown. Does the editome of these cells change? Are the ADARs somehow involved in this process? These are relevant questions that we are in the course of asking.
In this respect the project is highly innovative, combining innovative approaches such as Next Generation Sequencing, editome analysis and functional studies.