Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1.

Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.

Reference-free phylogeny from sequencing data.

MOTIVATION: Clustering of genetic sequences is one of the key parts of bioinformatics analyses. Resulting phylogenetic trees are beneficial for solving many research questions, including tracing the history of species, studying migration in the past, or tracing a source of a virus outbreak. At the same time, biologists provide more data in the raw form of reads or only on contig-level assembly. Therefore, tools that are able to process those data without supervision need to be developed. RESULTS: In this paper, we present a tool for reference-free phylogeny capable of handling data where no mature-level assembly is available. The tool allows distance calculation for raw reads, contigs, and the combination of the latter. The tool provides an estimation of the Levenshtein distance between the sequences, which in turn estimates the number of mutations between the organisms. Compared to the previous research, the novelty of the method lies in a newly proposed combination of the read and contig measures, a new method for read-contig mapping, and an efficient embedding of contigs.

circGPA: circRNA functional annotation based on probability-generating functions.

Recent research has already shown that circular RNAs (circRNAs) are functional in gene expression regulation and potentially related to diseases. Due to their stability, circRNAs can also be used as biomarkers for diagnosis. However, the function of most circRNAs remains unknown, and it is expensive and time-consuming to discover it through biological experiments. In this paper, we predict circRNA annotations from the knowledge of their interaction with miRNAs and subsequent miRNA-mRNA interactions. First, we construct an interaction network for a target circRNA and secondly spread the information from the network nodes with the known function to the root circRNA node. This idea itself is not new; our main contribution lies in proposing an efficient and exact deterministic procedure based on the principle of probability-generating functions to calculate the p-value of association test between a circRNA and an annotation term. We show that our publicly available algorithm is both more effective and efficient than the commonly used Monte-Carlo sampling approach that may suffer from difficult quantification of sampling convergence and subsequent sampling inefficiency. We experimentally demonstrate that the new approach is two orders of magnitude faster than the Monte-Carlo sampling, which makes summary annotation of large circRNA files feasible; this includes their reannotation after periodical interaction network updates, for example. We provide a summary annotation of a current circRNA database as one of our outputs. The proposed algorithm could be generalized towards other types of RNA in way that is straightforward.