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Gracjan Michlewski


Nila Roy Choudhury, Jakub Nowak, Carlos Augusto B. Alves.
Michlewski lab website

Regulation of MicroRNA Processing and Function

MicroRNAs (miRs) constitute a large family of short (21-23nt), conserved non-coding RNAs. They regulate gene expression by targeting partially complementary sequences in the mRNAs. Each microRNA has the capacity to regulate several, possibly hundreds, of mRNA targets, thus controlling a variety of biological processes, including cell cycle, developmental timing, differentiation, metabolism, neuronal patterning and ageing. In spite of the great effort to understand various biological roles of individual microRNAs, very little has been done to unravel the regulation of their biogenesis. Our group is focused on elucidating the cis and trans-acting factors that play significant roles in microRNA processing and function.
A number of mature microRNAs exhibit a tissue-specific pattern of expression, without an apparent tissue-specific pattern for their corresponding primary transcripts. This discrepancy is suggestive of post-transcriptional regulation of microRNA abundance. Recently, we have demonstrated that the brain-enriched expression of miR-7, which is processed from the ubiquitous pre-mRNA transcript, is supported by inhibition of its biogenesis in non-brain cells. We identified MSI2 and HuR proteins as inhibitors of miR-7 processing in non-neural cells. This is achieved through HuR-mediated binding of MSI2 to the conserved elements of miR-7 primary transcript. We confirmed the physiological relevance of this inhibitory mechanism in a cellular, neuronal differentiation system as well as in tissues from MSI2 KO mouse. Our data provide the first insight into Regulation of microRNA processing and function the regulation of brain-enriched microRNA processing by defined tissue-specific factors.

By combining a wide spectrum of molecular biology and biochemistry techniques, including functional assays in mammalian cultured cells, RNA deep sequencing, RNA chromatography combined with SILAC Mass Spectrometry, RNA structure probing and in vitro processing assays, we are dissecting the fine details of microRNA biogenesis pathways. Currently, we are investigating the mechanisms controlling the abundance of the brain-specific microRNAs, as well as the contribution of microRNAs to induced Pluripotent Stem (iPS) cell formation. If successful, our projects will have far reaching consequences for our understanding of how microRNAs regulate gene expression, providing novel cutting-edge avenues for future research and potential targets for novel therapies.

Selected publications:

Michlewski, G., Guil, S., Semple, C.A., and Cáceres, J.F. (2008) Posttranscriptional regulation of miRNAs harboring conserved terminal loops. Mol Cell 32, 383-393

Michlewski, G., and Cáceres, J.F. (2010) Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol 17, 1011-1018.

Choudhury, N.R., de Lima Alves, F., de Andrés-Aguayo, L., Graf, T., Cáceres, J.F., Rappsilber, J., and Michlewski, G. (2013) Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev 27, 24-38.