1. Genetics and Genomics
  2. Medicine
Download icon

SMA-miRs: miR-181a-5p, -324-5p, -451a are overexpressed in spinal muscular atrophy skeletal muscle and serum samples

  1. Emanuela Abiusi
  2. Paola Infante
  3. Cinzia Cagnoli
  4. Ludovica Lospinoso Severini
  5. Marika Pane
  6. Giorgia Coratti
  7. Maria Carmela Pera
  8. Adele D'Amico
  9. Federica Diano
  10. Agnese Novelli
  11. Serena Spartano
  12. Stefania Fiori
  13. Giovanni Baranello
  14. Isabella Moroni
  15. Marina Mora
  16. Maria Barbara Pasanisi
  17. Krizia Pocino
  18. Loredana Le Pera
  19. Davide D'amico
  20. Lorena Travaglini
  21. Francesco Ria
  22. Claudio Bruno
  23. Denise Locatelli
  24. Enrico Silvio Bertini
  25. Lucia Ovidia Morandi
  26. Eugenio Mercuri
  27. Lucia Di Marcotullio
  28. Francesco Danilo Tiziano  Is a corresponding author
  1. Università cattolica del Sacro Cuore, Italy
  2. Istituto Italiano di Tecnologia, Italy
  3. Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
  4. Università degli Studi di Roma La Sapienza"", Italy
  5. Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Italy
  6. Bambino Gesu' Children's Hospital IRCCS, Italy
  7. Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Italy
  8. CNR-Institute of Biomembranes, Italy
  9. EPFL Innovation Park, Switzerland
  10. Università Cattolica del Sacro Cuore, Italy
  11. IRCCS Istituto Giannina Gaslini, Italy
Research Article
  • Cited 0
  • Views 440
  • Annotations
Cite this article as: eLife 2021;10:e68054 doi: 10.7554/eLife.68054

Abstract

Background:

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor-neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally two-to-four copies), inversely related with the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Beside the SMN2 products, few other biomarkers have been evaluated so far, including some miRs.

Methods:

We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2-full length transcript levels in blood and age (SMA-score).

Results:

Over 100 miRs were differentially expressed in SMA muscle; three of them (HSA-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly up-regulated in serum of patients. The severity predicted by the SMA-score was related with that of the clinical classification at a correlation coefficient of 0.87 (p<10-5).

Conclusions:

miRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis; the SMA-miRs are likely actively released in the blood flow, even if their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: if confirmed, its use could be crucial for the routine prognostic assessment, also in pre-symptomatic patients.

Funding:

Telethon Italia (grant # GGP12116).

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Raw sequencing data are available at NCBI-SRA database; BioProject PRJNA748014

Article and author information

Author details

  1. Emanuela Abiusi

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9028-012X
  2. Paola Infante

    Center For Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Roma, Italy
    Competing interests
    No competing interests declared.
  3. Cinzia Cagnoli

    Clinical and Experimental Epileptology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6863-6687
  4. Ludovica Lospinoso Severini

    Department of Molecular Medicine, Università degli Studi di Roma La Sapienza"", Roma, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1032-5496
  5. Marika Pane

    Centro Clinico Nemo, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, roma, Italy
    Competing interests
    No competing interests declared.
  6. Giorgia Coratti

    Centro Clinico Nemo, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, roma, Italy
    Competing interests
    No competing interests declared.
  7. Maria Carmela Pera

    Centro Clinico Nemo, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, roma, Italy
    Competing interests
    No competing interests declared.
  8. Adele D'Amico

    Unit of Neuromuscular and Neurodegenerative Disorders, Dept. Neurosciences, Bambino Gesu' Children's Hospital IRCCS, Roma, Italy
    Competing interests
    No competing interests declared.
  9. Federica Diano

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    Competing interests
    No competing interests declared.
  10. Agnese Novelli

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    Competing interests
    No competing interests declared.
  11. Serena Spartano

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    Competing interests
    No competing interests declared.
  12. Stefania Fiori

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    Competing interests
    No competing interests declared.
  13. Giovanni Baranello

    Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    Competing interests
    No competing interests declared.
  14. Isabella Moroni

    Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    No competing interests declared.
  15. Marina Mora

    Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, milano, Italy
    Competing interests
    No competing interests declared.
  16. Maria Barbara Pasanisi

    Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, milano, Italy
    Competing interests
    No competing interests declared.
  17. Krizia Pocino

    Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
    Competing interests
    No competing interests declared.
  18. Loredana Le Pera

    Bioenergetics and Molecular Biotechnologies (IBIOM), CNR-Institute of Biomembranes, Bari, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0076-9878
  19. Davide D'amico

    Amazentis SA, EPFL Innovation Park, Losanne, Switzerland
    Competing interests
    Davide D'amico, Davide D'Amico is affiliated with Amazentis SA. The author has no financial interests to declare. At the time of study developement, Dr. D'Amico had an academic affiliation.
  20. Lorena Travaglini

    Unit of Neuromuscular and Neurodegenerative Disorders, Dept. Neurosciences, Bambino Gesu' Children's Hospital IRCCS, Roma, Italy
    Competing interests
    No competing interests declared.
  21. Francesco Ria

    Department of Translational Medicine and Surgery, Section of General Pathology, Università Cattolica del Sacro Cuore, roma, Italy
    Competing interests
    No competing interests declared.
  22. Claudio Bruno

    Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova, Italy
    Competing interests
    No competing interests declared.
  23. Denise Locatelli

    Clinical and Experimental Epileptology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    Competing interests
    No competing interests declared.
  24. Enrico Silvio Bertini

    Unit of Neuromuscular and Neurodegenerative Disorders, Dept. Neurosciences, Bambino Gesu' Children's Hospital IRCCS, Roma, Italy
    Competing interests
    No competing interests declared.
  25. Lucia Ovidia Morandi

    Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, milano, Italy
    Competing interests
    No competing interests declared.
  26. Eugenio Mercuri

    Centro Clinico Nemo, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, roma, Italy
    Competing interests
    No competing interests declared.
  27. Lucia Di Marcotullio

    Department of Molecular Medicine, Università degli Studi di Roma La Sapienza"", Roma, Italy
    Competing interests
    No competing interests declared.
  28. Francesco Danilo Tiziano

    Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy
    For correspondence
    francescodanilo.tiziano@unicatt.it
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5545-6158

Funding

Fondazione Telethon (GGP12116)

  • Francesco Danilo Tiziano

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: According to the ARRIVE guidelines, procedures were carried out to minimize discomfort and pain, in compliance with National (D.L. 116 Suppl 40/1992 and D.L. 26/2014) and International guidelines and laws (2010/63/EU Legislation for the protection of animals used for scientific purposes). The experimental protocols were approved by the Ethics Committee of the Fondazione IRCCS Istituto Neurologico C. Besta and by the Italian Ministry of Health (protocol numbers: 962/2016-PR and 1039/2020-PR).

Human subjects: Informed consent was obtained from patients for genetic analyses. The study was approved by the local Ethics Committee

Reviewing Editor

  1. Christopher Cardozo

Publication history

  1. Received: March 3, 2021
  2. Accepted: September 13, 2021
  3. Accepted Manuscript published: September 20, 2021 (version 1)
  4. Accepted Manuscript updated: September 23, 2021 (version 2)
  5. Version of Record published: October 1, 2021 (version 3)

Copyright

© 2021, Abiusi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 440
    Page views
  • 97
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    David Mauduit et al.
    Research Article

    Understanding how enhancers drive cell type specificity and efficiently identifying them is essential for the development of innovative therapeutic strategies. In melanoma, the melanocytic (MEL) and the mesenchymal-like (MES) states present themselves with different responses to therapy, making the identification of specific enhancers highly relevant. Using massively parallel reporter assays (MPRA) in a panel of patient-derived melanoma lines (MM lines), we set to identify and decipher melanoma enhancers by first focusing on regions with state specific H3K27 acetylation close to differentially expressed genes. An in-depth evaluation of those regions was then pursued by investigating the activity of overlapping ATAC-seq peaks along with a full tiling of the acetylated regions with 190 bp sequences. Activity was observed in more than 60% of the selected regions and we were able to precisely locate the active enhancers within ATAC-seq peaks. Comparison of sequence content with activity, using the deep learning model DeepMEL2, revealed that AP-1 alone is responsible for the MES enhancer activity. In contrast, SOX10 and MITF both influence MEL enhancer function with SOX10 being required to achieve high levels of activity. Overall, our MPRAs shed light on the relationship between long and short sequences in terms of their sequence content, enhancer activity, and specificity across melanoma cell states.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Jeffrey V Wong et al.
    Feature Article

    Making the knowledge contained in scientific papers machine-readable and formally computable would allow researchers to take full advantage of this information by enabling integration with other knowledge sources to support data analysis and interpretation. Here we describe Biofactoid, a web-based platform that allows scientists to specify networks of interactions between genes, their products, and chemical compounds, and then translates this information into a representation suitable for computational analysis, search and discovery. We also report the results of a pilot study to encourage the wide adoption of Biofactoid by the scientific community.