Functional annotation of the vlinc class of non-coding RNAs using systems biology approach

Laurent, Georges St.; Vyatkin, Yuri; Антонец, Денис; Ri, Maxim; Qi, Yanfei; Saik, Olga V.; Shtokalo, Dmitry; Hoon, Michiel de; Kawaji, Hideya; Itoh, Masayoshi; Lassmann, Timo; Arner, Peter; Forrest, Alistair R.R.; Nicolas, Estelle; McCaffrey, Timothy A.; Carninci, Piero; Hayashizaki, Yoshihide; Wahlestedt, Claes; Kapranov, Philipp

doi:10.1093/nar/gkw162

Cited by 35 publications

(54 citation statements)

References 44 publications

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“…Real targets of GLI1 would be expected to correlate with the GLI1 mRNA across a wide range of cell types, and the availability of a broad expression dataset across 833 human cell types and conditions generated by the FANTOM5 consortium allowed us to accomplish the testing of this assumption (Forrest et al, 2014). We calculated the Spearman correlation between the GLI1 mRNA and each target transcript as previously described (St Laurent et al, 2016). For PTCH1, HHIP, and PTCH2, the correlations were 0.47, 0.4, and 0.27, respectively.…”

Section: Identification Of Gli1 Target Genesmentioning

confidence: 99%

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

et al. 2018

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Hedgehog (HH) signaling is involved in many physiological processes, and pathway deregulation can result in a wide range of malignancies. Glioma‐associated oncogene 1 (GLI1) is a transcription factor and a terminal effector of the HH cascade. Despite its crucial role in tumorigenesis, our understanding of the GLI1 cellular targets is quite limited. In this study, we identified multiple new GLI1 target genes using a combination of different genomic surveys and then subjected them to in‐depth validation in human cancer cell lines. We were able to validate >90% of the new targets, which were enriched in functions involved in neurogenesis and regulation of transcription, in at least one type of follow‐up experiment. Strikingly, we found that RNA editing of GLI1 can modulate effects on the targets. Furthermore, one of the top targets, FOXS1, a gene encoding a transcription factor previously implicated in nervous system development, was shown to act in a negative feedback loop limiting the cellular effects of GLI1 in medulloblastoma and rhabdomyosarcoma cells. Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors. Consistently, high FOXS1 expression predicts longer relapse‐free survival in breast cancer. Overall, our findings open multiple new avenues in HH signaling pathway research and have potential for translational implications.

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Section: Identification Of Gli1 Target Genesmentioning

confidence: 99%

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

et al. 2018

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“…Some lncRNAs are encoded between genes and are known as long intergenic noncoding RNAs (lincRNAs) 85 . Intergenic noncoding RNAs that are greater than 50 kB in length are known as very long intergenic RNAs (vlincRNAs) 86 .…”

Section: Long Noncoding Rna (Lncrnas)mentioning

confidence: 99%

Non-coding RNAs as drug targets

Matsui

Corey

2016

Nat Rev Drug Discov

860

622

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Most of the human genome encodes RNA that does not code for protein. These noncoding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs targeting ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during development of technologies to target mRNA. Here, we will discuss the growing field of ncRNA – including microRNA, intronic RNA, repetitive RNA and long non-coding RNA - and assess the potential and challenges in their therapeutic exploitation.

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“…Recent reports have described v ery long intergenic n on- c oding (vlinc)RNAs expressed in numerous human tissues [21–23]. The vlincRNAs are RNA Pol II products that are nuclear, non-spliced, non-polyadenylated transcripts of >50 kb of contiguously expressed sequence that are not associated with protein coding genes.…”

Section: Introductionmentioning

confidence: 99%

“…The vlincRNAs are RNA Pol II products that are nuclear, non-spliced, non-polyadenylated transcripts of >50 kb of contiguously expressed sequence that are not associated with protein coding genes. The initial reports annotated 2,147 human vlincRNAs from 833 samples in the FANTOM5 dataset [23, 24]. A more recent study identified an additional 574 vlincRNAs expressed in childhood acute lymphoblastic leukemia [25].…”

Section: Introductionmentioning

confidence: 99%

Reciprocal monoallelic expression of ASAR lncRNA genes controls replication timing of human chromosome 6

Heskett

Smith

Spellman

et al. 2019

Preprint

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25 DNA replication occurs on mammalian chromosomes in a cell-type distinctive temporal 26 order known as the replication timing program. We previously found that disruption of the 27 noncanonical lncRNA genes ASAR6 and ASAR15 results in delayed replication timing 28 and delayed mitotic chromosome condensation of human chromosome 6 and 15, 29 respectively. ASAR6 and ASAR15 display random monoallelic expression, and display 30 asynchronous replication between alleles that is coordinated with other random 31 monoallelic genes on their respective chromosomes. Disruption of the expressed allele, 32 but not the silent allele, of ASAR6 leads to delayed replication, activation of the previously 33 silent alleles of linked monoallelic genes, and structural instability of human chromosome 34 6. In this report, we describe a second lncRNA gene (ASAR6-141) on human 35 chromosome 6 that when disrupted results in delayed replication timing in cis. ASAR6-36 141 is subject to random monoallelic expression and asynchronous replication, and is 37 expressed from the opposite chromosome 6 homolog as ASAR6. ASAR6-141 RNA, like 38 ASAR6 and ASAR15 RNAs, contains a high L1 content and remains associated with the 39 chromosome territory where it is transcribed. Three classes of cis-acting elements control 40 proper chromosome function in mammals: origins of replication, centromeres; and 41 telomeres, which are responsible for replication, segregation and stability of all 42 chromosomes. Our work supports a fourth type of essential chromosomal element, 43 "Inactivation/Stability Centers", which express ASAR lncRNAs responsible for proper 44 replication timing, monoallelic expression, and structural stability of each chromosome. 45 3 46 Author summary 47 Mammalian cells replicate their chromosomes during a highly ordered and cell type-48 specific program. Genetic studies have identified two long non-coding RNA genes, 49 ASAR6 and ASAR15, as critical regulators of the replication timing program of human 50 chromosomes 6 and 15, respectively. There are several unusual characteristics of the 51 ASAR6 and ASAR15 RNAs that distinguish them from other long non-coding RNAs, 52 including: being very long (>200 kb), lacking splicing of the transcripts, lacking 53 polyadenylation, and being retained in the nucleus on the chromosomes where they are 54 made. ASAR6 and ASAR15 also have the unusual property of being expressed from only 55 one copy of the two genes located on homologous chromosome pairs. Using these 56 unusual characteristics shared between ASAR6 and ASAR15, we have identified a 57 second ASAR lncRNA gene located on human chromosome 6, which we have named 58 ASAR6-141. ASAR6-141 is expressed from the opposite chromosome 6 homolog as 59 ASAR6, and disruption of the expressed allele results in delayed replication of 60 chromosome 6. ASAR6-141 RNA had previously been annotated as vlinc273. The very 61 long intergenic non-coding (vlinc)RNAs represent a recently annotated class of RNAs that 62 are long (>50 kb), non-spliced, and non-polyade...

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Functional annotation of the vlinc class of non-coding RNAs using systems biology approach

Cited by 35 publications

References 44 publications

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

Non-coding RNAs as drug targets

Reciprocal monoallelic expression of ASAR lncRNA genes controls replication timing of human chromosome 6

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