Pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in early T cell development

• Published in: PloS one Vol. 3; no. 10; p. e3592
• Main Authors: Liu, Gwen, Min, Hyeyoung, Yue, Sibiao, Chen, Chang-Zheng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.10.2008; Public Library of Science (PLoS)
• Subjects: Adenosine; Animals; Base Sequence; Biosynthesis; Caenorhabditis elegans; CD4 antigen; CD8 antigen; Cell Biology; Cell Differentiation - genetics; Cells (biology); Cells, Cultured; Developmental Biology; Gene families; Gene sequencing; Genes; Hematopoiesis - genetics; Homology; Humans; Immunology; In vivo methods and tests; Laboratories; Lymphocytes; Lymphocytes T; Male; Medicine; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - chemistry; MicroRNAs - physiology; miRNA; Models, Biological; Molecular Biology; Molecular Sequence Data; Mutation; Nucleic Acid Conformation; Nucleotides; Pharmacology; Rodents; Seeds; Sequence Homology, Nucleic Acid; Stem cells; T cells; T-Lymphocytes - metabolism; T-Lymphocytes - physiology; Thymus; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003592

Mature miRNAs can often be classified into large families, consisting of members with identical seeds (nucleotides 2 through 7 of the mature miRNAs) and highly homologous approximately 21-nucleotide (nt) mature miRNA sequences. However, it is unclear whether members of a miRNA gene family, which encode identical or nearly identical mature miRNAs, are functionally interchangeable in vivo. We show that mir-181a-1, but not mir-181c, can promote CD4 and CD8 double-positive (DP) T cell development when ectopically expressed in thymic progenitor cells. The distinct activities of mir-181a-1 and mir-181c are largely determined by their unique pre-miRNA loop nucleotides-not by the one-nucleotide difference in their mature miRNA sequences. Moreover, the activity of mir-181a-1 on DP cell development can be quantitatively influenced by nucleotide changes in its pre-miRNA loop region. We find that both the strength and the functional specificity of miRNA genes can be controlled by the pre-miRNA loop nucleotides. Intriguingly, we note that mutations in the pre-miRNA loop regions affect pre-miRNA and mature miRNA processing, but find no consistent correlation between the effects of pre-miRNA loop mutations on the levels of mature miRNAs and the activities of the mir-181a-1/c genes. These results demonstrate that pre-miRNA loop nucleotides play a critical role in controlling the activity of miRNA genes and that members of the same miRNA gene families could have evolved to achieve different activities via alterations in their pre-miRNA loop sequences, while maintaining identical or nearly identical mature miRNA sequences.