bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2024–05–05
two papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons.
  2. Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.
  1. Genes Dev. 2024 Apr 30.
    The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons.
    Wen Xiao, Reem Halabi, Chia-Ho Lin, Mohammad Nazim, Kyu-Hyeon Yeom, Douglas L Black.
      Synaptic function in neurons is modulated by local translation of mRNAs that are transported to distal portions of axons and dendrites. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is broadly expressed across cell types, almost exclusively as a nuclear long noncoding RNA. We found that in differentiating neurons, a portion of Malat1 RNA redistributes to the cytoplasm. Depletion of Malat1 using antisense oligonucleotides (ASOs) stimulates the expression of particular pre- and postsynaptic proteins, implicating Malat1 in their regulation. Neuronal Malat1 is localized in puncta of both axons and dendrites that costain with Staufen1 protein, similar to neuronal RNA granules formed by locally translated mRNAs. Ribosome profiling of cultured mouse cortical neurons identified ribosome footprints within a 5' region of Malat1 containing short open reading frames. The upstream-most reading frame (M1) of the Malat1 locus was linked to the GFP-coding sequence in mouse embryonic stem cells. When these gene-edited cells were differentiated into glutamatergic neurons, the M1-GFP fusion protein was expressed. Antibody staining for the M1 peptide confirmed its presence in wild-type neurons and showed that M1 expression was enhanced by synaptic stimulation with KCl. Our results indicate that Malat1 serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.
    Keywords:  Malat1; RNA localization; lncRNA; local translation; micro-ORF
    DOI:  https://doi.org/10.1101/gad.351557.124
  2. Genome Biol. 2024 Apr 29. 25(1): 111
    Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.
    Nechama Wieder, Elston N D'Souza, Alexandra C Martin-Geary, Frederik H Lassen, Jonathan Talbot-Martin, Maria Fernandes, Sonia P Chothani, Owen J L Rackham, Sebastian Schafer, Julie L Aspden, Daniel G MacArthur, Robert W Davies, Nicola Whiffin.
       BACKGROUND: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity.
    RESULTS: We investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated.
    CONCLUSIONS: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.
    Keywords:  5’ untranslated regions; 5’UTR; Dosage sensitivity; Loss-of-function; Translational regulation; Upstream open reading frame; uORF
    DOI:  https://doi.org/10.1186/s13059-024-03248-0
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