Genetic variation and RNA structure regulate microRNA biogenesis

Fernández, Noemí; Cordiner, Ross A.; Young, Robert S.; Hug, Nele; Macías, Sara; Cáceres, Javier F.

doi:10.1038/ncomms15114

Cited by 66 publications

(57 citation statements)

References 68 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The widespread reduction of miRNAs in human tumors has been attributed to dysregulation of the DROSHA/DGCR8 microprocessor complex as a result of the many pathways that regulate microprocessor components, e.g., p72 is sequestered by YAP in the Hippo pathway in a cell-density-dependent manner (Mori, et al 2014). RNA binding proteins also regulate pri-miRNA accessibility (Fernandez, et al 2017). …”

Section: The Chronology Of Mirna Discovery Was Recently Reviewed (Drumentioning

confidence: 99%

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

Klinge

2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

Abstract:The human genome is 'pervasively transcribed' leading to a complex array of noncoding RNAs (ncRNAs) that far outnumber coding mRNAs. ncRNAs have regulatory roles in transcription and post-transcriptional processes as well numerous cellular functions that remain to be fully described. Best characterized of the 'expanding universe' of ncRNAs are the ~ 22 nucleotide microRNAs (miRNAs) that base-pair to target mRNA's 3' untranslated region within the RNA-induced silencing complex (RISC) and block translation and may stimulate mRNA transcript degradation. Long non-coding RNAs (lncRNAs) are classified as >200 nucleotides in length, but range up to several kb and are heterogeneous in genomic origin and function.LncRNAs fold into structures that interact with DNA, RNA, and proteins to regulate chromatin dynamics, protein complex assembly, transcription, telomere biology, and splicing. Some lncRNAs act as sponges for miRNAs and decoys for proteins. Nuclear-encoded lncRNAs can be taken up by mitochondria and lncRNAs are transcribed from mtDNA. Both miRNAs and lncRNAs are dysregulated in endocrine cancers. This review provides an overview on the current understanding of the regulation and function of selected lncRNAs and miRNAs, and their interaction, in endocrine-related cancers: breast, prostate, endometrial, and thyroid.

show abstract

Section: The Chronology Of Mirna Discovery Was Recently Reviewed (Drumentioning

confidence: 99%

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

Klinge

2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…SRSF3 protein expression is upregulated in putative CD133+ colon cancer stem cells in comparison to CD133-cells and its depletion slowed down cell proliferation of Caco-2 colorectal cancer cells, supporting the role of SRSF3 in tumorigenicity of colon cancer (61). A single G-to-A mutation in the terminal loop of pri-mir-30c-1 in breast and gastric cancer patients has been shown to alter the secondary pri-miRNA structure facilitating SRSF3 binding and processing by Drosha (62). Similarly, a C-to-T mutation within the CNNC motif downstream of pri-miR-16 has been associated with chronic lymphocytic leukemic (63).…”

Section: Discussionmentioning

confidence: 78%

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Ratnadiwakara

Engel

Jardé

et al. 2019

Preprint

View full text Add to dashboard Cite

Almost a half of microRNAs (miRNAs) in mammalian cells are generated from polycistronic primary transcripts encoding more than one miRNA. Mature miRNAs from polycistronic clusters frequently regulate complementary sets of target mRNAs. How the processing of individual miRNAs within the clusters is controlled to give rise to distinct miRNA levels in vivo is not fully understood. Our investigation of SRSF3 (Serine-Arginine Rich Splicing Factor 3) regulated noncoding RNAs in pluripotent cells identified miR-17-92 cluster as a key SRSF3 target, SRSF3 binding to the CNNC motif 17-18nt downstream of the miRNA stem loop. Here we show that SRSF3 binding site context, not merely the distance from the stem loop, within primary transcript is a critical determinant of the processing efficiency of distinct miRNAs derived from the miR-17-92 cluster. SRSF3 specifically enhanced the processing of two paralog miRNAs, miR-17 and miR-20a, targeting overlapping mRNAs including the cell cycle inhibitor CDKN1A/p21. Functional analysis demonstrated that SRSF3 inhibits CDKN1A expression and promotes cell cycle and self-renewal through the miRNA processing pathway both in normal pluripotent stem cells and cancer cells. Strikingly, analysis of colorectal cancer tumour-normal pairs demonstrated that the SRSF3-regulated miRNA processing pathway is present in a large proportion of colorectal cancer patients and distinguishes poorly differentiated high-grade tumours. Our research uncovers a critical role of SRSF3 in selective processing of miR-17-92 miRNAs, which mechanistically and functionally links SRSF3 to hallmark features of cancer.

show abstract

“…Although the apical region of the miRNA does not have a function as critical as the seed, polymorphisms located in this particular region can have relevant effects on the structural conformation of the pre-miRNA hairpin [13]. In other words, SNPs in the apical region can modify the efficiency with which the Drosha processing machinery, mediating the initial slicing of the hairpin, is recruited.…”

Section: Discussionmentioning

confidence: 99%

Variability in porcine microRNA genes and its association with mRNA expression and lipid phenotypes

Mármol-Sánchez¹,

Guan

Quintanilla

et al. 2020

Preprint

View full text Add to dashboard Cite

25 Background 26 Mature microRNAs (miRNAs) play an important role in repressing the expression of a 27 wide range of protein coding transcripts by promoting their degradation or inhibiting 28 their translation into functional proteins. The presence of segregating polymorphisms 29 inside miRNA loci and their corresponding 3'UTR binding sites might disrupt canonical 30 conserved miRNA-mRNA pairing, thus modifying gene expression patterns. 31 Results 32We aimed to investigate the variability of miRNA genes and their putative binding sites 33 by analyzing whole-genome sequences from 120 pigs and wild boars from Europe and 34 Asia. In total, 285 SNPs residing within miRNA loci were detected. From these, 221 35 were located in precursor regions, whereas 52 and 12 mapped to mature and seed 36 regions, respectively. Moreover, a total of 109,724 polymorphisms were identified in 37 predicted 7mer-m8 miRNA binding sites within porcine 3'UTRs. A principal 38 components analysis revealed a clear genetic divergence between Asian and European 39 samples, which was particularly strong for 3'UTR sequences. We also observed that 40 miRNA genes show reduced polymorphism compared with other non-miRNA regions. 41To assess the potential consequences of miRNA polymorphisms, we sequenced the 42 genomes of 5 Duroc pigs and, by doing so, we identified 15 miRNA SNPs that were 43 genotyped in the offspring (N = 345) of the five boars. Association analyses between 44 miRNA SNPs and hepatic and muscle microarray data allowed us to identify 4 45 polymorphisms displaying significant associations. Particularly interesting was the 46 rs319154814 polymorphism (G/A), located in the apical loop of the ssc-miR-326 47 3 precursor sequence. This polymorphism is predicted to cause a subtle hairpin 48 rearrangement that improves the accessibility to processing enzymatic factors. 49 Conclusions 50 Porcine miRNA genes show a reduced variability, particularly in the seed region which 51 plays a critical role in miRNA binding. Although it is generally assumed that SNPs 52 mapping to the seed region are the ones with the strongest consequences on mRNA 53 expression, we show that a SNP mapping to the apical region of ssc-miR-326 is 54 associated with the mRNA expression of several of its predicted targets. This result 55 suggests that porcine miRNA variability mapping within and outside the seed region 56 could have important regulatory effects on gene expression. 57 58 59 60 61 62 63 64 65 66 67 4 Background 68 Mature microRNA transcripts (miRNAs) are short (~22 nt) non-coding RNAs 69 which play an essential role in the regulation of gene expression [1]. During the 70 biogenesis of miRNAs, one strand of the miRNA duplex binds to the guide-strand 71 channel of an Argonaute protein forming an miRNA-induced silencing complex 72 (miRISC) with the ability of repressing mRNA expression through binding to specific 73 3'UTR target sites [2]. In postembryonic cells, this repressor mechanism mainly acts by 74 destabilizing the mRNA through decapping and poly(A)-tail...

show abstract

Genetic variation and RNA structure regulate microRNA biogenesis

Cited by 66 publications

References 68 publications

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Variability in porcine microRNA genes and its association with mRNA expression and lipid phenotypes

Contact Info

Product

Resources

About