DGCR8 HITS-CLIP reveals novel functions for the Microprocessor

Macías, Sara; Plass, Mireya; Stajuda, Agata; Michlewski, Gracjan; Eyras, Eduardo; Cáceres, Javier F.

doi:10.1038/nsmb.2344

Cited by 195 publications

(238 citation statements)

References 54 publications

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“…Our findings complement previous work on L1 post-transcriptional regulation by Caceres and colleagues 26,38 , which identified multiple direct binding sites in the L1 5′ UTR for the microprocessorcomplex subunit DGCR8 (ref. 38), which binds and cleaves L1 RNA 26 .…”

Section: Discussionsupporting

confidence: 91%

“…38), which binds and cleaves L1 RNA 26 . Our results expand this work and suggest a scenario in which DGCR8 binds to double-stranded RNA structures of the 5′ UTR of L1 RNA and cleaves L1 in the nucleus; L1 transcripts that escape DGCR8-mediated control are transported out of the nucleus, where a second miR-mediated mechanism regulates their expression levels and represses their effects in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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VOLUME 22 NUMBER 10 OCTOBER 2015 nature structural & molecular biology a r t i c l e s microRNAs (miRs) are a class of small (~22-nt) genomically encoded molecules that inhibit translational initiation and stimulate decay of mRNA targets 1,2 . miRs are transcribed by RNA polymerase II and processed by the RNase III enzymes-Dicer and Drosha with its binding partner, DGCR8-to produce short double-stranded RNAs in the nucleus. One strand associates with the Argonaute (Ago) protein, thus forming the miR-mediated silencing complex (miRISC). miRs guide the pairing of miRISC, with imperfect complementarity, to sequences in target mRNAs, thus resulting in their subsequent destabilization and translational repression of the target 3 . The 'seed sequence' , at nucleotides 2-8, is a key determinant for miRISC-target recognition 4,5 . Recent data have shown that 35-40% of miR-binding sites are found in 3′ untranslated regions (UTRs), 40-50% in coding regions and <5% in 5′-UTR regions of mRNAs 6,7 . More than 60% of the human transcriptome has been predicted to be under miR regulation, thus making this post-transcriptional control pathway as important as protein pathways in the regulation of cell functions 2 . It is clear that miRs have essential roles in regulating diverse functions in normal and diseased cells 8,9 .L1 belongs to the most abundant class of autonomous transposable elements 10 . Human L1 contains two open reading frames, ORF1 and ORF2, which encode a protein with RNA-binding and nucleotide acid-chaperone activity (ORF1) 11 and a protein with endonuclease and reverse-transcriptase activities (ORF2) 12-15 , respectively. L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 . Mechanisms that operate at different levels in gene-expression hierarchies have been selected to control transposition-mediated mutagenesis and mitigate the potential negative effects of newly inserted elements. In germ cells, a specific small-RNA subtype (piwi-interacting RNAs (piRNAs)) efficiently counteracts L1 activity, but these RNAs are not expressed in nongerm cells 21,22 . Somatic cells attenuate element mobilization by DNA methylation of the L1 promoter 23 . Other methods of regulation are mediated by APOBEC proteins 24,25 , microprocessor interactions 26 and Ago-mediated RNA interference in mouse embryonic stem cells 27 . L1-promoter silencing is greatly attenuated, and L1 transcription is reactivated in hypomethylated cells, such as cancer cells and tumor-initiating cells, and is also reactivated during reprogramming [28][29][30] . Because miRs act as regulators of g...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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“…Post-transcriptional modifications add an additional level of regulation to NSC maintenance and differentiation. Growing evidence suggest that miRNA-independent functions of the microprocessor are conserved mechanisms that regulate several cellular processes in the nervous system and other tissues Han et al, 2009;Karginov et al, 2010;Knuckles et al, 2012;Macias et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

“…Drosha can bind and cleave hairpin loops in mRNAs Han et al, 2009;Knuckles et al, 2012;Macias et al, 2012). In silico analysis (Evofold) (Pedersen et al, 2006) revealed two evolutionarily conserved hairpins in the mRNA of NFIB, a short 20 bases hairpin in the 5' untranslated region (hereafter refer to as 5' UTR HP) and a longer hairpin of 83 bases in the 3' untranslated region (hereafter refer to as 3'…”

Section: Drosha Binds and Cleaves The Nfib Mrna Regulating Expressionmentioning

confidence: 99%

“…However, Drosha can also cleave and directly destabilize mRNAs encoding proteins that regulate cell fate decisions Han et al, 2009;Knuckles et al, 2012;Macias et al, 2012). During embryonic development, Drosha maintains embryonic NSCs in an undifferentiated, multipotent state by targeting and cleaving the mRNA of the proneural factor Ngn2 (Knuckles et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

et al. 2016

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SUMMARYMulti-lineage neuronal, astrocytic and oligodendrocytic potential is considered a neural stem cell (NSC) trait. However, hippocampal NSCs generate neurons and astrocytes but not oligodendrocytes in vivo and how this is regulated is unknown. Here we show that the RNAseIII Drosha is an intrinsic regulator of stem cell maintenance and differentiation in the adult mouse hippocampus. Inactivation of Drosha results in exhaustion of the NSC pool, premature arrest of neurogenesis, and induction of oligodendrocyte fate commitment. Drosha silences Nuclear Factor IB (NFIB) in hippocampal NSCs by targeting a double-stranded hairpin in the NFIB mRNA, thereby repressing its expression in a Dicer and miRNA-independent manner. We show that NFIB is required and sufficient for oligodendrocyte fate and knockdown of NFIB rescues neurogenesis by Drosha-deficient hippocampal NSCs. Our findings reveal a novel mechanism for stem cell maintenance and oligodendrocyte fate restriction in the adult hippocampus.3

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Regulation of primary microRNA processing

2018

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Edited by Wilhelm JustMicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular mechanisms involved in miRNA biogenesis and mode of action have been elucidated in the past two decades. Similar to many cellular pathways, miRNA processing and function can be globally or specifically regulated at several levels and by numerous proteins and RNAs. Given their role as fine-tuning molecules, it is essential for miRNA expression to be tightly regulated in order to maintain cellular homeostasis. Here, we review our current knowledge of the first step of their maturation occurring in the nucleus and how it can be specifically and dynamically modulated.

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DGCR8 HITS-CLIP reveals novel functions for the Microprocessor

Cited by 195 publications

References 54 publications

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

Regulation of primary microRNA processing

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