Long Noncoding RNAs & Circular RNAs

Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations

Guarnerio J1, Bezzi M1, Jeong JC2, Paffenholz SV1, Berry K1, Naldini MM1, Lo-Coco F3, Tay Y4, Beck AH2, Pandolfi PP5.
Cell.
Malin Akerblom
Time
12:00pm
Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect noncoding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.
Long Noncoding RNAs & Circular RNAs
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malinakerblom
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DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions

Huang W1, Thomas B2, Flynn RA3, Gavzy SJ1, Wu L1, Kim SV1, Hall JA1, Miraldi ER1,4,5,6, Ng CP1, Rigo FW7, Meadows S8, Montoya NR1, Herrera NG1, Domingos AI9, Rastinejad F10, Myers RM8, Fuller-Pace FV11, Bonneau R4,5,6, Chang HY3, Acuto O2, Littman DR1,12.
Nature.
John Gagnon
Time
12:00pm
T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5–RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5–RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.
Long Noncoding RNAs & Circular RNAs
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jgagnon
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Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed

Rybak-Wolf A1, Stottmeister C1, Glažar P1, Jens M1, Pino N2, Giusti S2, Hanan M3, Behm M4, Bartok O3, Ashwal-Fluss R3, Herzog M1, Schreyer L1, Papavasileiou P1, Ivanov A1, Öhman M4, Refojo D5, Kadener S3, Rajewsky N6.
Mol Cell.
Malin Akerblom
Time
12:00pm
Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers.
Long Noncoding RNAs & Circular RNAs
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malinakerblom
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Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Tan JY, Vance KW, Varela MA, Sirey T, Watson LM, Curtis HJ, Marinello M, Alves S, Steinkraus BR, Cooper S, Nesterova T, Brockdorff N, Fulga TA, Brice A, Sittler A, Oliver PL, Wood MJ, Ponting CP, Marques AC.
Nat Struct Mol Biol.
Matias Alvarez-Saavedra
Time
12:00pm
What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA–mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.
Long Noncoding RNAs & Circular RNAs
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A long noncoding RNA protects the heart from pathological hypertrophy

Han P1, Li W1, Lin CH2, Yang J3, Shang C4, Nurnberg ST4, Jin KK4, Xu W5, Lin CY4, Lin CJ4, Xiong Y4, Chien HC4, Zhou B6, Ashley E4, Bernstein D7, Chen PS3, Chen HS8, Quertermous T4, Chang CP9.
Nature
Dimitre Simeonov
Time
12:00pm
The role oflong noncodingRNA (lncRNA)in adult heartsis unknown; also unclearis how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription1 , including myosin heavy chain 7 (Myh7), which encodes molecularmotor proteins for heart contraction2 . Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA–chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundantin adult hearts. Pathological stress activates the Brg1–Hdac–Parp chromatin repressor complex3 toinhibitMhrttranscriptionin the heart. Such stress-inducedMhrtrepression is essential for cardiomyopathy to develop: restoringMhrtto the prestress level protects the heart from hypertrophy and failure.Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy3 . Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain thatis crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized—but not naked—DNA. This dual-binding feature of helicase enables a competitive inhibitionmechanism bywhichMhrtsequestersBrg1 fromitsgenomicDNA targets to prevent chromatin remodelling. A Mhrt–Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanismin human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatinremodelling factors, and establish a new paradigm for lncRNA– chromatin interaction.
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Enhancer RNA Facilitates NELF Release from Immediate Early Genes

Schaukowitch K, Joo JY, Liu X, Watts JK, Martinez C, Kim TK.
Mol Cell.
Koh Fujinaga
Time
12:00pm
Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons. eRNAs are synthesized prior to the culmination of target gene transcription and interact with the NELF complex. Knockdown of eRNAs expressed at neuronal enhancers impairs transient release of NELF from the specific target promoters during transcriptional activation, coinciding with a decrease in target mRNA induction. The enhancer-promoter interaction was unaffected by eRNA knockdown. Instead, chromatin looping might enable eRNAs to act locally at a specific promoter. Our findings highlight the spatiotemporally regulated action mechanism of eRNAs during early transcriptional elongation.
 
Long Noncoding RNAs & Circular RNAs
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Fujinaga
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Regulation of pri-miRNA Processing by a Long Noncoding RNA Transcribed from an Ultraconserved Region

Liz J, Portela A, Soler M, Gómez A, Ling H, Michlewski G, Calin GA, Guil S, Esteller M.
Mol Cell.
David Wu
Time
12:00pm
Noncoding RNAs (ncRNAs) control cellular programs by affecting protein-coding genes, but evidence increasingly points to their involvement in a network of ncRNA-ncRNA interactions. Here, we show that a long ncRNA, Uc.283+A, controls pri-miRNA processing. Regulation requires complementarity between the lower stem region of the pri-miR-195 transcript and an ultraconserved sequence in Uc.283+A, which prevents pri-miRNA cleavage by Drosha. Mutation of the site in either RNA molecule uncouples regulation in vivo and in vitro. We propose a model in which lower-stem strand invasion by Uc.283+A impairs microprocessor recognition and efficient pri-miRNA cropping. In addition to identifying a case of RNAdirected regulation of miRNA biogenesis, our study reveals regulatory networks involving different ncRNA classes of importance in cancer.
 
Long Noncoding RNAs & Circular RNAs
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dwu
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The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation

Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, Jiang Z, Xu J, Liu Q, Cao X.
Science
Kathrin Schumann
Time
12:00pm
Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.
 
Long Noncoding RNAs & Circular RNAs
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kathrin
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N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells

Yang Wang, Yue Li, Julia I. Toth, Matthew D. Petroski, Zhaolei Zhang & Jing Crystal Zhao
Nature Cell Biology
Frank Xiao
Time
12:00pm
N 6 -methyladenosine (m6A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes1 . m6A modification is involved in cell fate determination in yeast2,3 and embryo development in plants4,5 . Its mammalian function remains unknown but thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs) show m6A modification6,7 and m6A demethylases are required for mammalian energy homeostasis and fertility8,9. We identify two proteins, the putative m6A MTase, methyltransferase-like 3 (Mettl3; ref. 10), and a related but uncharacterized protein Mettl14, that function synergistically to control m6A formation in mammalian cells. Knockdown of Mettl3 and Mettl14 in mouse embryonic stem cells (mESCs) led to similar phenotypes, characterized by lack of m6A RNA methylation and lost self-renewal capability. A large number of transcripts, including many encoding developmental regulators, exhibit m6A methylation inversely correlated with mRNA stability and gene expression. The human antigen R (HuR) and microRNA pathways were linked to these effects. This gene regulatory mechanism operating in mESCs through m6A methylation is required to keep mESCs at their ground state and may be relevant to thousands of mRNAs and lncRNAs in various cell types.
Long Noncoding RNAs & Circular RNAs
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XiaoF
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