The RNA-binding protein QKI5 regulates primary miR-124-1 processing via a distal RNA motif during erythropoiesis

MicroRNA (miRNA) biogenesis is finely controlled by complex layers of post-transcriptional regulators, including RNA-binding proteins (RBPs). Here, we show that an RBP, QKI5, activates the processing of primary miR-124-1 (pri-124-1) during erythropoiesis. QKI5 recognizes a distal QKI response element and recruits Microprocessor through interaction with DGCR8. Furthermore, the recruited Microprocessor is brought to pri-124-1 stem loops by a spatial RNA-RNA interaction between two complementary sequences. Thus, mutations disrupting their base-pairing affect the strength of QKI5 activation. When erythropoiesis proceeds, the concomitant decrease of QKI5 releases Microprocessor from pri-124-1 and reduces mature miR-124 levels to facilitate erythrocyte maturation. Mechanistically, miR-124 targets TAL1 and c-MYB, two transcription factors involved in normal erythropoiesis. Importantly, this QKI5-mediated regulation also gives rise to a unique miRNA signature, which is required for erythroid differentiation. Taken together, these results demonstrate the pivotal role of QKI5 in primary miRNA processing during erythropoiesis and provide new insights into how a distal element on primary transcripts affects miRNA biogenesis.

[1]  E. Lai,et al.  Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. , 2011, Molecular cell.

[2]  J. Steitz,et al.  The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones , 2014, Cell.

[3]  Patrick R. Wright,et al.  Two separate modules of the conserved regulatory RNA AbcR1 address multiple target mRNAs in and outside of the translation initiation region , 2014, RNA biology.

[4]  G. Hannon,et al.  Small RNA sorting: matchmaking for Argonautes , 2011, Nature Reviews Genetics.

[5]  S. Richard,et al.  QUAKING KH Domain Proteins as Regulators of Glial Cell Fate and Myelination , 2005, RNA biology.

[6]  Yue Feng,et al.  Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism , 2003, The EMBO journal.

[7]  Yue Feng,et al.  QKI binds MAP1B mRNA and enhances MAP1B expression during oligodendrocyte development. , 2006, Molecular biology of the cell.

[8]  J. Frampton,et al.  Coordination of erythropoiesis by the transcription factor c-Myb. , 2006, Blood.

[9]  Michelle S. Scott,et al.  Protection of p27Kip1 mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation , 2005, Nature Neuroscience.

[10]  Hsien-Da Huang,et al.  miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions , 2013, Nucleic Acids Res..

[11]  Hyeshik Chang,et al.  Mono-Uridylation of Pre-MicroRNA as a Key Step in the Biogenesis of Group II let-7 MicroRNAs , 2012, Cell.

[12]  R. Shiekhattar,et al.  The Microprocessor complex mediates the genesis of microRNAs , 2004, Nature.

[13]  David P. Bartel,et al.  Beyond Secondary Structure: Primary-Sequence Determinants License Pri-miRNA Hairpins for Processing , 2013, Cell.

[14]  Albrecht Bindereif,et al.  Analysis of RNA-protein complexes by oligonucleotide-targeted RNase H digestion. , 2002, Methods.

[15]  V. Narry Kim,et al.  Characterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processing , 2006, Nucleic acids research.

[16]  Thomas Tuschl,et al.  Structure-function studies of STAR family Quaking proteins bound to their in vivo RNA target sites. , 2013, Genes & development.

[17]  V. Kim,et al.  Functional Anatomy of the Human Microprocessor , 2015, Cell.

[18]  Andreas W. Schreiber,et al.  The RNA Binding Protein Quaking Regulates Formation of circRNAs , 2015, Cell.

[19]  M. Brand,et al.  Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis , 2012, Oncogene.

[20]  S. Richard,et al.  The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells , 2013, Molecular and Cellular Biology.

[21]  M. Rosenfeld,et al.  The RNA-binding Protein KSRP Promotes the Biogenesis of a Subset of miRNAs , 2016 .

[22]  D. Bartel,et al.  The Menu of Features that Define Primary MicroRNAs and Enable De Novo Design of MicroRNA Genes. , 2015, Molecular cell.

[23]  Guodong Yang,et al.  E2F1 and RNA binding protein QKI comprise a negative feedback in the cell cycle regulation , 2011, Cell cycle.

[24]  V. Kim,et al.  Regulation of microRNA biogenesis , 2014, Nature Reviews Molecular Cell Biology.

[25]  Monika Heiner,et al.  The RNA-Binding Protein QKI Suppresses Cancer-Associated Aberrant Splicing , 2014, PLoS genetics.

[26]  S. Guil,et al.  The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a , 2007, Nature Structural &Molecular Biology.

[27]  C. Joo,et al.  Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. , 2008, Molecular cell.

[28]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[29]  Lai Wei,et al.  Regulation of microRNA expression and abundance during lymphopoiesis. , 2010, Immunity.

[30]  Yue Feng,et al.  Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein , 2010, Proceedings of the National Academy of Sciences.

[31]  Yuehua Wu,et al.  Long noncoding RNAs with snoRNA ends. , 2012, Molecular cell.

[32]  G. Hannon,et al.  Processing of primary microRNAs by the Microprocessor complex , 2004, Nature.

[33]  Hui Zhou,et al.  starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data , 2013, Nucleic Acids Res..

[34]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[35]  Scott B. Dewell,et al.  Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP , 2010, Cell.

[36]  Yonghong Xiao,et al.  STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA. , 2012, Genes & development.

[37]  S. Barik,et al.  MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. , 2011, Molecular and cellular pharmacology.

[38]  R. Ueda,et al.  Prognostic impact of microRNA-145 down-regulation in adult T-cell leukemia/lymphoma. , 2014, Human pathology.

[39]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[40]  Ola R. Snøve,et al.  Reliable prediction of Drosha processing sites improves microRNA gene prediction. , 2007, Bioinformatics.

[41]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[42]  R. Gregory,et al.  A Biogenesis Step Upstream of Microprocessor Controls miR-17∼92 Expression , 2015, Cell.

[43]  Fang Wang,et al.  Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. , 2006, Biochemical and biophysical research communications.

[44]  E. Wagner,et al.  Antisense RNA‐mediated transcriptional attenuation occurs faster than stable antisense/target RNA pairing: an in vitro study of plasmid pIP501. , 1994, The EMBO journal.

[45]  R. Lavker,et al.  MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia , 2008, Proceedings of the National Academy of Sciences.

[46]  R. Gregory,et al.  A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway , 2013, Nature.

[47]  Rolf Backofen,et al.  CopraRNA and IntaRNA: predicting small RNA targets, networks and interaction domains , 2014, Nucleic Acids Res..

[48]  C. Croce,et al.  MicroRNA expression and function in cancer. , 2006, Trends in molecular medicine.

[49]  Chun Xing Li,et al.  Differential expression of components of the microRNA machinery during mouse organogenesis. , 2005, Biochemical and biophysical research communications.

[50]  Stefan L Ameres,et al.  Diversifying microRNA sequence and function , 2013, Nature Reviews Molecular Cell Biology.

[51]  C. F. Bennett,et al.  Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents , 2003, The Journal of Biological Chemistry.