Proc Natl Acad Sci U S A. 2014;111:7319���24. 2010;8:e1000384. For example, the lncRNA Airn, originally identified in mouse as promoting genomic imprinting of the maternal protein-coding Igf2r gene cluster, where Airn itself is encoded [96], was later shown to act independently of its RNA [97]. 2A). PubMed Central�� Would you like email updates of new search results? Cell Rep. 2017;18:2280���8. PLoS Genet. b The lncRNAs ncRNA-a3 and ncRNA-a7 functionally and physically associate with the Mediator complex to promote gene expression of their respective target genes. Transcription Factor MafB Coordinates Epidermal Keratinocyte Differentiation. Miyai M, Hamada M, Moriguchi T, Hiruma J, Kamitani-Kawamoto A, Watanabe H, Hara-Chikuma M, Takahashi K, Takahashi S, Kataoka K. J Invest Dermatol. Epidermal differentiation gene regulatory networks controlled by MAF and MAFB. However, despite the rapid growth of the field, intriguing questions remain, such as whether all or just a fraction of the existing lncRNAs have a function, or whether this function can be exclusively ascribed to the RNA product of the lncRNA gene. Recruitment of Transcription Factors: When an lncRNA sequence is located near to transcription factor binding site, the lncRNA transcript can hybridize to both that location and to a transcription factor protein, thus enhancing . Previous studies showed lncRNA can bind to YBX1 and influence the transcriptional activities of YBX1 . All authors wrote the manuscript and approved the final version. P Value. This is the first book to provide a broad framework for obtaining an in depth understanding of the state-of-the-art knowledge on abnormalities of non-coding RNAs found to be associated with colorectal cancer pathogenesis. Human skin cancers, the most common type of tumors, represent a significant health burden. The deadliest is unquestionably melanoma. Linking long noncoding RNA localization and function. (A) Four possible cis-regulatory mechanisms mediated by lncRNA genes.Cis-regulation of nearby genes can be achieved directly by the lncRNA transcript, by cis-regulatory elements overlapping with the lncRNA gene such as an enhancer (Groff et al., 2016), or the lncRNA promoter itself (Engreitz et al., 2016; Paralkar et al., 2016), or by the transcription of the lncRNA (Latos et al., 2012). Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. 2014;71:2625���39. The lncRNA APOLO interacts with the transcription factor WRKY42 to trigger root hair cell expansion in response to cold Author links open overlay panel Michaël Moison 1 6 Javier Martínez Pacheco 2 6 Leandro Lucero 1 6 Camille Fonouni-Farde 1 Johan Rodríguez-Melo 3 Natanael Mansilla 1 Aurélie Christ 4 Jérémie Bazin 4 Moussa Benhamed 4 . The role of lncRNAs in nuclear organization is well exemplified by the lncRNA NEAT1, which, as mentioned above, drives the formation of nuclear bodies known as paraspeckles. Chen LL. Keywords: colon cancer, DNA methylation, transcription factor, lncRNA, drug response, survival. Methods Differentially expressed long non-coding RNAs (lncRNAs) related to bladder cancer . 2014;15:749���60. For example, the mouse lncRNA Evf2 is transcribed from an ultraconserved distal enhancer, which specifically binds the transcription factor DLX2, forming a transcriptional complex, and binds an enhancer, thereby inducing expression of the adjacent protein-coding gene DLX5/6 . 2013;494:497���501. Skourti-Stathaki K, Proudfoot NJ. An inducible long noncoding RNA amplifies DNA damage signaling. Cell. Bharti SK, Khan I, Banerjee T, Sommers JA, Wu Y, Brosh Jr RM. 2017;547:241���5. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. 2015;6:7743. Despite the advances in treatment modalities, the prognosis of GBM is (B) In vivo skin xenografts generated from CRISPR/Cas9-targeted primary keratinocytes with a control sgRNA or two different combinations of sgRNAs targeting MAF and MAFB (crMAF:crMAFB 47 or crMAF:MAFB 35), harvested 21 days post-seeding, and immunostained for differentiation markers keratin 10 and filaggrin (red) and MAF or MAFB (green). The system will first examine whether or not the input lncRNA IDs or names are correct and show the information in the message box and then identify common TFs based on the hypergeometric test. 2) Select experiment: Pull down the selective menu to restrict the analysis on the selected cell line (tissue) or condition. FG_H/FG_S. 2020 Jan 29;69(1):1-10. doi: 10.1538/expanim.19-0076. More recently, using a similar approach to that described for Airn, genome editing of the lncRNA Lockd locus was used to investigate whether the lncRNA functions through its transcript or DNA elements contained in its genomic locus [99]. Currently, three major functional principles can be assigned to lncRNA loci (): (1) either the RNA is the functional biomolecule and interacts with other components in the cell, for example DNA, proteins or RNAs, (2) a gene regulatory element is embedded in the transcription body of a lncRNA gene and the activity of the lncRNA gene directs the activity of the regulatory element or (3) the . Quijada P, Trembley MA, Misra A, Myers JA, Baker CD, Pérez-Hernández M, Myers JR, Dirkx RA Jr, Cohen ED, Delmar M, Ashton JM, Small EM. Despite not being translated into proteins, lncRNAs are functional molecules. This book will be invaluable and entertaining for anyone who is involved in the care of patients with cystic fibrosis. Transcription factor or other DNA-binding protein in the ChIP-Seq experiment. RNA-seq, GRO-seq, ChIP-seq), the investigators observed that functional interactions between neighbouring genes are frequent, both for lncRNAs and protein-coding loci, and that such cross-talk relies on different manners of function [100]. where (1)is the number of all annotated lncRNA genes (transcripts) in Homo sapiens;(2) is the number of annotated lncRNA genes (transcripts) that contain at least one ChIP-Seq peak of the TF in their regulatory regions;(3) is the number of lncRNA genes (transcripts) that users input;(4) is the number of lncRNA genes (transcripts) in the inputted lncRNAs that have at least one peak of the TF within their regulatory regions. Mol Cell. Paralkar VR, Taborda CC, Huang P, Yao Y, Kossenkov AV, Prasad R, Luan J, Davies JO, Hughes JR, Hardison RC, et al. (A) Transcriptional activity modulates DNA methylation and thereby alters occupation of DNA binding factors within the gene body, for example CTCF. CONCR (cohesion regulator noncoding RNA) is also included in the small number of lncRNAs reported so far to modulate an enzymatic activity [54]. Development. We review emerging mechanistic views of lncRNAs in gene regulation in the cell nucleus. Nat Commun. Bonasio R, Shiekhattar R. Regulation of transcription by long noncoding RNAs. The lncRNAs are broadly defined as noncoding RNA molecules longer than 200 nucleotides. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. 2010;142:409���19. Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma Genes (Basel). Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, et al. Finally, a competing endogenous RNA (ceRNA) network incorporating transcription factors (TFs) was constructed. • LncRNAs are generally expressed at low levels • LncRNA sequences are not well conserved between species. LncRNA CTD-3252C9.4 inhibits IFI6 expression through binding with its transcription factor IRF1. Hypergeometric test (this method is usually applied to assess gene ontology or pathway enrichment for a list of protein-coding genes) is used to identify common TFs for a set of lncRNA genes or transcripts. The co-expression coefficients between the transcription factors and lncRNA973 were generally greater than 0.99, indicating possible regulatory relationships between them. linc-RoR is highly expressed in the cytoplasm of differentiated ESCs and sequesters miR-145 that in turn suppresses the miRNA-mediated degradation of mRNAs for the core transcription factors Oct4, Sox2, and Nanog (see Figure 1H in main text). (J) Eighty genes whose expression changes with knockdown of both MAF and MAFB and that are associated with both MAF and MAFB ChIP-seq peaks (see also Figure S6). Nature. Another way of recognizing chromatin DNA by lncRNAs is the formation of RNA���DNA triplexes [81]. Enhancer RNA facilitates NELF release from immediate early genes. LncMAP analysis was performed, and E2F4 was found to be the potential transcription factor that mediated the modulation of HAND2‐AS1 on C16orf74 expression (Table 3 ). In this volume expert researchers in the field detail many of the methods which are now commonly used to study RNA. Ulitsky I. Evolution to the rescue. The long noncoding RNA Neat1 is required for mammary gland development and lactation. CAS�� This study intended to examine the potential tumor-suppressing role of ZNF503 antisense RNA 1 (ZNF503-AS1) in bladder cancer, which may be implicated in the regulation of Ca2+ homeostasis. FIGURE 1. Curr Opin Plant Biol. The landscape of long noncoding RNAs in the human transcriptome. However, only the identification of the RNA sequences and structural elements that confer lncRNAs with these capabilities, as well as the determination of the biochemical and biophysical properties of the lncRNA-containing complexes, will lend further insight into the mechanisms that lncRNAs employ for gene regulation. Compared to microRNAs or snoRNAs that exhibit strong conservation across diverse species, lncRNAs lack strong conservation, which is often cited as evidence of nonfunctionality [2, 3]. Article�� lncRNA: Transcription Splicing Localization and Function. For the lncRNAs found to regulate mRNA transcription through the formation of R-loops, the mechanism of regulation is in cis as the R-loop formed by the transcription of the lncRNA regulates the expression of the closest protein-coding gene, transcribed in antisense orientation with respect to the lncRNA. However, lncRNAs are temporally and spatially expressed and regulated, and motif-based sequence analysis cannot capture the dynamic regulation of lncRNAs by TFs in different cell lines. MTF1, a transcription factor, drives mRNA expression in response to toxic heavy metals [ 42 ]. Although the number of loci evaluated in the study is still very limited considering the thousands of lncRNA���mRNA gene pairs present in the genome [101], none of the lncRNA loci included in the study seemed to require the lncRNA itself for the investigated cis-regulatory function [100]. Alternatively, lncRNA-dependent regulation could also be considered in terms of cost-effectiveness, as RNAs are energetically less expensive to produce for the cell in comparison with proteins. Kotzin JJ, Spencer SP, McCright SJ, Kumar DB, Collet MA, Mowel WK, Elliott EN, Uyar A, Makiya MA, Dunagin MC, et al. A schematic workflow is shown in Figure 3. PubMed�� Scale bar, 50 μm. Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, McDonel PE, Guttman M, Lander ES. Mol Cell. Nature. CAS�� Users can thus infer which TFs are likely to be common transcription regulators of the set of lncRNAs. Mol Cell. For instance, several lncRNAs act in cooperation with heterogeneous nuclear ribonucleoproteins (hnRNPs) [23,24,25,26], a large family of RNA-binding proteins involved in different cellular processes, including alternative splicing, mRNA stability, and transcriptional regulation [27]. Transcriptional overlap does not occur at the other imprinted genes in the Igf2r cluster���Slc22a2 and Slc22a3���where the silencing properties of Airn might reside in its RNA [97, 98]. Pregnancy-induced noncoding RNA (PINC) associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation. Here we showed that the lncRNA MALAT1 was critical for Sp1 transcriptional activa-tion of the LTBP3. (F) Multi-dimensional GSEA conducted on published epidermal regulator gene sets against the three differentiation signatures (-log, (A) GSEA of genes downregulated in MAF:MAFB-depleted tissue overlaps with gene sets of known epidermal differentiation regulators. (H) Disease ontology enrichment observed for genes associated with MAF and MAFB peaks. The Mediator complex: a central integrator of transcription. Glioma is the most common and deadly tumor in central nervous system. Sun L, Goff LA, Trapnell C, Alexander R, Lo KA, Hacisuleyman E, Sauvageau M, Tazon-Vega B, Kelley DR, Hendrickson DG, et al. Melanoma addiction to the long non-coding RNA SAMMSON. (B) MAF (top, red) and MAFB (bottom, blue) ChIP-seq tracks at epidermal TF genes. For several reasons (reviewed in [46]), PRC2 is the most studied chromatin complex with respect to the functional role of lncRNAs in epigenetic regulation of gene expression. Nature. A large repertoire of lncRNAs are able to interact with chromatin-modifying complexes. More recently, other lncRNAs have been reported to recruit chromatin modifiers in an RNA���DNA triplex-dependent manner, at promoters of both neighbouring and distal genes [83,84,85]. Also, lncRNAs are more rapidly produced than proteins in response to stimuli���a favourable dynamic that could confer faster cellular responses. lncRNA-transcription factor interactions can either recruit or evict transcription . Widespread transcription at neuronal activity-regulated enhancers. 2012;81:145���66. Users can select (i) the source organism and the TF, (ii) the cell line in which the ChIP experiment was performed, (iii) the regulatory region of lncRNA genes (e.g., 2000 bp upstream and 1000 bp downstream from its TSS), and (iv) the lncRNA ID/name to be used to display the results.
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