Frequency preference in miRNA-mRNA interaction models: competition and cooperativity effects

SZISCHIK CANDELA; FERRO ELSI; BOSIA CARLA; ALEJANDRA C VENTURA

Berlin

Conferencia; 21st International Conference on Systems Biology; 2022

A number ofrecent studies have highlighted that living cells are inherentlydynamic.Live-cell time-lapse microscopy and fluorescent reporter genes have allowed totrack thedynamic behavior of specific molecules over time, thereby uncovering a picturewhere manyregulatory proteins undergo pulses of activation and deactivation. Recentquantitativestudies have mathematically investigated the implications of pulsatility andperiodicityin diverse signaling contexts. Results demonstrate that oscillatory signals areableto carrykey biological information encoded in the shape of pulses. It has been shownthatfeaturessuch as the duration, frequency and amplitude can determine the behavior ofsignalingpathways. MicroRNAs are small RNA molecules that do not code for proteins andregulatetheir target, messenger RNA (mRNA), through a post-transcriptional mechanism[1].It isgenerally accepted that miRNAs repress gene expression by promoting thedegradationof targetmRNA and/or inhibiting its translation [2]. Thousands of mature miRNAs havebeenobserved inhumans, and regulatory circuits involving miRNAs are increasingly beinguncoveredacting in key biological processes, such as development and differentiation[3].MiRNAs playfundamental roles in pathological contexts related to tumorigenesis, viralinfection,and neurological diseases [4]. A single miRNA regulates multiple target genes,anda gene istypically targeted by several different miRNAs. An mRNA molecule often presentsmultiplebinding sites relative to a specific miRNA, making the extent of repressiondependenton how many of such sites are bound and thus conferring cooperative propertiesto theinteraction between a miRNA and its target [5]. We theoretically addresspulsatilesignaling withinmiRNA-mediated regulation focusing on the role of oscillation frequency andinvestigatingits interplay with significant features of miRNA-mRNA interaction, namelycooperativebinding and competition between targets. We feed the system with pulsatilemiRNAexpression, and we compute frequency-dependent responses in terms ofbiologicallyrelevantquantities. Specifically, we focus on observables that characterize thestrength ofmiRNA-mediatedrepression, such as the level of unbound target mRNA and the fold-repression.Our results indicate that modulation some parameters that control competitionandcooperativity could serve as a tuning mechanism: it can shift and sharpen thefrequencypreferenceresponse, leading to non-intuitive effects. These results can also be addressexperimentallyby quantifying target fold-repression by time-lapse microscopy and usingoptogeneticsto induce a pulsatile miR-20a expression and transfecting fluorescent targets.[1] Bartel,D. P. Cell 116, 281–297 (2004). [2] He, L. & Hannon, G. J. Nat. Rev.Genet. 5,522–531 (2004). [3] Ferro, E. & Enrico Bena, C.a& Grigolon, S. & Bosia, C. Cells 8, 1540(2019). [4] Tealdi, S. & Ferro, E. & Campa,C. C. &Bosia, C. Biomolecules 12, 213 (2022).[5] Bosia C. & Pagnani A. & Zecchina R. PLoSONE 8, 6 (2013).