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Journal of Molecular Neuroscience

, Volume 67, Issue 2, pp 295–304 | Cite as

Network Profiling of Brain-Expressed X-Chromosomal MicroRNA Genes Implicates Shared Key MicroRNAs in Intellectual Disability

  • Thainá Fernandez Gonçalves
  • Rafael Mina Piergiorge
  • Jussara Mendonça dos Santos
  • Jaqueline Gusmão
  • Márcia Mattos Gonçalves Pimentel
  • Cíntia Barros Santos-RebouçasEmail author
Article
  • 77 Downloads

Abstract

MicroRNAs are endogenous non-protein-coding RNA molecules that regulate post-transcriptional gene expression. The majority of human miRNAs are brain-expressed and chromosome X is enriched in miRNA genes. We analyzed the genomic regions of 12 brain-expressed pre-miRNAs located on chromosome X coding for 18 mature miRNAs, aiming to investigate the involvement of miRNA sequence variants on X-linked intellectual disability (XLID). Genomic DNA samples from 135 unrelated Brazilian males with intellectual disability, suggestive of X-linked inheritance, were amplified through polymerase chain reaction and sequenced by Sanger sequencing. Although no sequence variations have been identified, suggesting an intense selective pressure, further computational analysis evidenced that eight mature miRNAs (miR-221-3p/222-3p, miR-223-3p, miR-361-5p, miR-362-5p, miR-504-5p.1, miR-505-3p.1, and miR-505-3p.2) act as critical regulators of X-linked and autosomal ID genes in a fully connected network. Enrichment approaches identify transcription regulation, nervous system development, and regulation of cell proliferation as the main common biological processes among the target ID genes. Besides, a clustered chromosomal coverage of the imputed miRNAs target genes and related regulators was found on X chromosome. Considering the role of miRNAs as fine-tuning regulators of gene expression, a systematic analysis of miRNAs’ expression could uncover part of the genetic landscape subjacent to ID, being urgently necessary in patients with this condition, particularly XLID.

Keywords

Intellectual disability MicroRNA Brain Chromosome X 

Notes

Acknowledgements

The authors thank the families who participated in this study for their kind cooperation.

Funding Information

This work was supported by funds from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES), and Centro de Produção da Universidade do Estado do Rio de Janeiro (CEPUERJ).

Compliance with Ethical Standards

The Institutional Ethics Committee has approved all the procedures and samples were obtained after signature of an informed consent by the guardians of each patient included in this study.

Conflict of Interests

The authors declare that they have no conflict of interest.

Supplementary material

12031_2018_1235_MOESM1_ESM.pdf (649 kb)
Supplementary Figure 1 Genomic sequences of the pre-miRNAs included in this study obtained from a patient. The miRNA-3p and -5p sequences are highlighted with a solid rectangle and with a dashed rectangle, respectively. (PDF 648 kb)
12031_2018_1235_MOESM2_ESM.png (483 kb)
Supplementary Figure 2 Molecular interaction network to common X-linked ID genes and miRNAs by Cytoscape 3.6.1. mir-221-3p/mir-222-3p have the same seed sequence and were considered together as a cluster. (PNG 483 kb)
12031_2018_1235_MOESM3_ESM.png (1.3 mb)
Supplementary Figure 3 Molecular interaction network to common autosomal ID genes and miRNAs found with Target Scan by Cytoscape 3.6.1. mir-221-3p/mir-222-3p have the same seed sequence and were considered together as a cluster. (PNG 1321 kb)
12031_2018_1235_MOESM4_ESM.png (1.4 mb)
Supplementary Figure 4 Enriched pathways for the three Gene Ontology (GO) categories (Biological Process, BP; Molecular Function, MF; Cellular Component, CC) by Enrichr (Chen et al. 2013; Kuleshov et al. 2016). Only results that presented adjusted p value < 0.01 and at least ten genes were represented. (PNG 1408 kb)
12031_2018_1235_MOESM5_ESM.png (823 kb)
Supplementary Figure 5 Biological Process (BP) terms (adjusted p value < 0.01 and at least ten genes) represented hierarchically with BLAST2GO (Conesa et al. 2005). (PNG 823 kb)
12031_2018_1235_MOESM6_ESM.png (7.1 mb)
Supplementary Figure 6 Ideograms representing the chromosomal localization of the filtered target genes associated with DI and their regulators (miRNAs and TFs) in the human genome obtained by Phenogram software. (PNG 7275 kb)
12031_2018_1235_Fig2_ESM.png (226 kb)
Supplementary Figure 7

Venn diagram representing the number of miRNAs target genes shared between analyzes performed with TargetScan and mirDIP databases. As mirDIP database does not apply the annotation ‘hsa-miR-505-3p.1’ and ‘hsa-miR-505-3p.2’, only hsa-miR-505-3p was recovered. (PNG 225 kb)

12031_2018_1235_MOESM7_ESM.tif (267 kb)
High Resolution Image (TIF 266 kb)
12031_2018_1235_MOESM8_ESM.pptx (54 kb)
Supplementary Figure 8 Individual chromosome length (base pairs), number of coding genes and number of miRNA genes in comparison to the whole human genome (%). (DOCX 18 kb) (PPTX 54 kb)
12031_2018_1235_MOESM9_ESM.docx (19 kb)
Supplementary Table 1 Sequence of primers (5′ to 3′) used for miRNA screening and their position on the X chromosome. (DOCX 18 kb)
12031_2018_1235_MOESM10_ESM.docx (26 kb)
Supplementary Table 2 Conservation of the X-chromosomal miRNAs expressed in cortex and cerebellum analyzed in this study among different species (data collected from TargetScan 7.1). (DOCX 26 kb)
12031_2018_1235_MOESM11_ESM.docx (28 kb)
Supplementary Table 3 Text mining results from all PubMed articles associated with the eight shared miRNAs through pubmed.mineR tool (Rani et al. 2015). Only the articles that presented the terms “microRNA”, “miR”, “expression”, “gene expression”, “target”, “inhibiting” or “regulation” were preserved in the study. The expressions containing “target” and the target genes names listed in these interactions were obtained. (DOCX 27 kb)
12031_2018_1235_MOESM12_ESM.docx (30 kb)
Supplementary Table 4 Summary of the variants previously found in the mature and seed sequences of the 18 selected brain-expressed X-chromosomal microRNA genes, as well as the number of diseases causally related to each miRNA. (DOCX 29 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Thainá Fernandez Gonçalves
    • 1
  • Rafael Mina Piergiorge
    • 2
  • Jussara Mendonça dos Santos
    • 1
  • Jaqueline Gusmão
    • 3
  • Márcia Mattos Gonçalves Pimentel
    • 1
  • Cíntia Barros Santos-Rebouças
    • 1
    Email author
  1. 1.Servgen, Department of Genetics, Institute of Biology Roberto Alcantara GomesState University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Functional Genomics and Bioinformatics Laboratory, FiocruzOswaldo Cruz InstituteRio de JaneiroBrazil
  3. 3.Laboratory of Fisheries Genetics and Conservation, Department of Genetics, Institute of Biology Roberto Alcantara GomesState University of Rio de JaneiroRio de JaneiroBrazil

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