Alena Shkumatava

Regulatory non-coding RNA.

Alena Shkumatava is a Senior Lecturer and Principal Investigator at the Institute of Cell Biology, University of Edinburgh. She studied Biology and Genetics at the University of Vienna and obtained her PhD at EMBL Heidelberg, where she investigated molecular mechanisms of neuronal development in zebrafish in the laboratory of Carl Neumann. She then pursued postdoctoral research with David Bartel at the Whitehead Institute for Biomedical Research/MIT, focusing on small and long non-coding RNAs in vertebrate development.

From 2013 to 2023, she led a research group at Institut Curie in Paris, before relocating her lab to Edinburgh in 2023. 

portrait photo of Alena Shkumatava
Alena Shkumatava

Alena's research explores conserved mechanisms of non-coding RNA function in development, physiology, and disease. Research approaches in her laboratory integrate molecular genetics, RNA biochemistry, evolutionary biology, and other innovative technologies. Her group has uncovered fundamental principles of RNA biology, developed widely adopted tools for mapping RNA–protein interactions, and revealed how conserved non-coding RNA elements regulate gene expression, chromatin, and cell fate decisions

Anett Ladanyi, Lee Chen and Letizia Cogliandro


The central goal of the Shkumatava laboratory is to understand the cellular and molecular functions of regulatory non-coding RNA. Regulatory non-coding RNA comes in many flavours from small to long RNAs and can also be embedded within coding RNAs from messenger RNA to viral RNA. These regulatory RNAs govern diverse developmental, physiological and pathological processes across the kingdom of life.

lncRNAs

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides produced by RNA Polymerase II with limited or no protein-coding potential. They occupy a vast proportion of eukaryotic genome transcriptional units and regulate essential cellular processes. However, the principles underlying their molecular functions often remain enigmatic. We use lncRNAs as a paradigm to discover functional non-coding RNA elements and to discover their molecular mechanism of action.

Conserved sequence elements in lncRNAs

One strategy to pinpoint functional non-coding RNA elements is through sequence conservation. However, lncRNA sequences undergo rapid evolutionary turnover resulting in only a small set of ‘ultra-conserved’ lncRNAs that show detectable sequence conservation in vertebrates1,2. Using this approach, we identified a conserved element within a lncRNA that regulates animal behaviour from zebrafish to mouse. The element works through nearly perfect base-complementarity with a microRNA that mediates targeted destruction of the microRNA (Figure 1)3. 

We continue to explore such ultra-conserved elements to reveal lncRNAs and embedded regulatory elements with key cellular functions. 

Functional conservation of lncRNAs with divergent sequences 

Many lncRNAs are syntenic—occupying conserved genomic positions—even when their sequences diverge. Strikingly, these divergent lncRNAs can carry out conserved biological functions, though the molecular determinants remain hidden. In addition to guiding RNA binding3, lncRNA can also function through interaction with proteins. We devised the incPRINT methodology which allows for the identification of RNA specific RNA-binding proteins4. Using this approach, we found novel interactors and effectors of Xist, the lncRNA essential for mammalian sex chromosome dosage compensation4. In addition to linear RNA sequence motifs that are recognised by some proteins, structural RNA elements are also the basis of RNA-protein and RNA-RNA interactions. We recently found that syntologous lncRNAs with no detectable sequence homology carry out similar biological functions mediated by a set of conserved lncRNA-protein interactions5. A key aim of our laboratory is to uncover these cryptic determinants of non-sequence-conserved RNA function.


cartoon drawing of brain section from mutant mice

Figure 1: Failure to degrade miR-29b through a highly conserved non-coding RNA element in the cerebellum results in motor learning defects. 

Viral non-coding RNA

RNA viruses rely on regulatory non-coding RNA for their replication and host infection. Viral 5'- and 3'- untranslated regions (UTRs) contain specific regulatory sequence motifs whose recognition by proteins impacts post-transcriptional regulation of gene expression, modulation of subcellular localization, translation efficiency, and RNA stability. The identification of such sequence motifs and associated host RNA-binding proteins therefore both present an opportunity to understand essential viral-host mechanisms and discover potential vulnerabilities in viral infection, replication and immune suppression. We identified a set of human proteins associated within the untranslated regions of SARS-CoV-2 by employing quantitative incPRINT. This approach revealed host RNA-binding proteins supporting or inhibiting viral propagation. We currently strive to expand this approach to other viruses with similar host-switching potential. The identification of conserved regulatory noncoding RNA sequences, RNA structural elements and associated proteins is an important asset in understanding viral transmission and can enable preparation for future pandemics. 

  1. Ulitsky, I., Shkumatava, A., Jan, C.H., Sive, H. & Bartel, D.P. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147, 1537-50 (2011).
  2. Constanty, F. & Shkumatava, A. lncRNAs in development and differentiation: from sequence motifs to functional characterization. Development 148(2021).
  3. Bitetti, A. et al. MicroRNA degradation by a conserved target RNA regulates animal behavior. Nat Struct Mol Biol 25, 244-251 (2018).
  4. Graindorge, A. et al. In-cell identification and measurement of RNA-protein interactions. Nat Commun10, 5317 (2019).

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