Initially considered as “junk” DNA, it is now clear that the non-protein coding part of the human genome, which comprises about 98 % of the ~3·109 DNA bases, is extensively transcribed and gives rise to numerous non-coding RNAs. Our general objective is to understand how these non-coding RNAs regulate gene expression on the molecular level, and to what extend this regulation impacts on cellular function. In particular, we investigate how microRNAs (miRNAs), small non-coding RNAs with a critical role in post-transcriptional gene regulation, influence B lympocyte development and function. In addition, we are interested in the molecular mechanisms underlying miRNA biogenesis.
MicroRNAs in B lymphocytes
MiRNAs are small, non-coding RNAs that mediate posttranscriptional silencing of a predicted 60% of protein-coding genes in mammals. Here, we aim to decipher how miRNAs impact on the sensitive processes that control B cell maturation and activation, which together ensure the establishment of a competent humoral immune system. We approach this topic with a two-pronged strategy, using gain-of-function as well as loss-of-function experiments and in vivo models to study transforming and physiologically relevant miRNAs.
In canonical miRNA biogenesis, miRNA genes give rise to long primary transcripts (pri-miRNAs) that are characterized by one or several stem-loop structures in which the mature miRNAs are embedded. These stem-loop structures are recognized and cleaved by the nuclear Microprocessor, composed of the RNase DROSHA and its co-factor DGCR8. While most pri-miRNA are well defined by structural and sequence features, it is still not fully understood how cells can discriminate miRNA-like stem-loop structures from authentic primary miRNAs, and how accessory proteins beyond the core components shape the mature miRNA transcriptome.
In this context we have recently characterized a novel mechanism called cluster assistance that significantly broadens the Microprocessor substrate specificity. Here, a bona fide pri-miRNA stem-loop structure functions as a cis-regulatory element that can license or enhance the processing of neighboring suboptimal pri-miRNAs within polycistronic clusters. However, we are far from understanding the mechanism underlying this phenomenon.
The hematopoietic miR-15 family members, encoded by the miR-15a/miR-16-1 and miR-15b/miR-16-2 clusters, regulate progenitor B cell proliferation by direct targeting expression and signaling of the critical growth factor receptor for IL-7.
Using a gain-of-function and a loss-of-function approach, we demonstrate that levels of the miR-26 family determine whether early B cells proliferate or
A novel mechanism we have called "cluster assistance" describes how suboptimal primary miRNA stem-loops can be processed when paired with another standard miRNA
hairpin on the same transcript.
Hutter K, Lohmüller M, Jukic A, Eichin F, Avci S, Labi V, Szabo TG, Hoser SM, Hüttenhofer A, Villunger A, Herzog S. Mol Cell. 2020 Jun 4;78(5):876-889.e6. doi: 10.1016/j.molcel.2020.05.011. PMID: 32502422
Biocenter Innsbruck (CCB)
Medical University Innsbruck
Division of Developmental Immunology
Tel.: +43 (0) 512-9003-70381
FAX: +43 (0) 512-9003-73960