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Evidence for the biogenesis of more than 1,000 novel human microRNAs

Marc R Friedländer1234*, Esther Lizano1234, Anna JS Houben1234, Daniela Bezdan25, Mónica Báñez-Coronel1234, Grzegorz Kudla6, Elisabet Mateu-Huertas1234, Birgit Kagerbauer1234, Justo González1234, Kevin C Chen78, Emily M LeProust9, Eulàlia Martí1234 and Xavier Estivill1234*

Author Affiliations

1 Genomics and Disease Group, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, Barcelona 08003, Catalonia, Spain

2 Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, Barcelona 08003, Catalonia, Spain

3 Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (CIBERESP), Barcelona 08003, Catalonia, Spain

4 Hospital del Mar Research Institute (IMIM), Dr. Aiguader 88, Barcelona 08003, Catalonia, Spain

5 Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, Barcelona 08003, Catalonia, Spain

6 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland

7 Department of Genetics, Rutgers, State University of New Jersey, Frelinghuysen Road 174, Piscataway, NJ 08854, USA

8 BioMaPS Institute for Quantitative Biology, Rutgers, State University of New Jersey, Frelinghuysen Road 174, Piscataway, NJ 08854, USA

9 Genomics Solution Unit, Agilent Technologies Inc., Santa Clara, CA 95051, USA

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Genome Biology 2014, 15:R57  doi:10.1186/gb-2014-15-4-r57

Published: 7 April 2014

Abstract

Background

MicroRNAs (miRNAs) are established regulators of development, cell identity and disease. Although nearly two thousand human miRNA genes are known and new ones are continuously discovered, no attempt has been made to gauge the total miRNA content of the human genome.

Results

Employing an innovative computational method on massively pooled small RNA sequencing data, we report 2,469 novel human miRNA candidates of which 1,098 are validated by in-house and published experiments. Almost 300 candidates are robustly expressed in a neuronal cell system and are regulated during differentiation or when biogenesis factors Dicer, Drosha, DGCR8 or Ago2 are silenced. To improve expression profiling, we devised a quantitative miRNA capture system. In a kidney cell system, 400 candidates interact with DGCR8 at transcript positions that suggest miRNA hairpin recognition, and 1,000 of the new miRNA candidates interact with Ago1 or Ago2, indicating that they are directly bound by miRNA effector proteins. From kidney cell CLASH experiments, in which miRNA-target pairs are ligated and sequenced, we observe hundreds of interactions between novel miRNAs and mRNA targets. The novel miRNA candidates are specifically but lowly expressed, raising the possibility that not all may be functional. Interestingly, the majority are evolutionarily young and overrepresented in the human brain.

Conclusions

In summary, we present evidence that the complement of human miRNA genes is substantially larger than anticipated, and that more are likely to be discovered in the future as more tissues and experimental conditions are sequenced to greater depth.