scholarly journals The long non-coding RNA Dali is an epigenetic regulator of neural differentiation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Vladislava Chalei ◽  
Stephen N Sansom ◽  
Lesheng Kong ◽  
Sheena Lee ◽  
Juan F Montiel ◽  
...  
Keyword(s):  
Neural Differentiation ◽  
Noncoding Rna ◽  
Dna Methyltransferase ◽  
Large Scale ◽  
Cpg Island ◽  
Methylation Status ◽  
Neuroblastoma Cells ◽  
Regulatory Elements ◽  
Protein Coding ◽  
Non Coding Rna

Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.

scholarly journals Discovering long noncoding RNA predictors of anticancer drug sensitivity beyond protein-coding genes

2019 ◽  
Vol 116 (44) ◽  
pp. 22020-22029 ◽  
Author(s):  
Aritro Nath ◽  
Eunice Y. T. Lau ◽  
Adam M. Lee ◽  
Paul Geeleher ◽  
William C. S. Cho ◽  
...  
Keyword(s):  
Anticancer Drug ◽  
Noncoding Rna ◽  
Large Scale ◽  
Drug Response ◽  
Cancer Cell Line ◽  
Systematic Evaluation ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Clinical Biomarkers ◽  
Response Predictors

Large-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long noncoding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue lineage, or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that 2 lncRNAs, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-epidermal growth factor receptor (EGFR) drug response.

scholarly journals Mutations in gene regulatory elements linked to human limb malformations

2019 ◽  
Vol 57 (6) ◽  
pp. 361-370
Author(s):  
Karol Nowosad ◽  
Ewa Hordyjewska-Kowalczyk ◽  
Przemko Tylzanowski
Keyword(s):  
Regulatory Elements ◽  
Regulatory Function ◽  
Protein Coding ◽  
Coding Regions ◽  
Technological Advances ◽  
Non Coding Rna ◽  
Limb Malformations ◽  
Gene Regulatory Elements ◽  
Chromatin Organisation ◽  
Human Limb

Most of the human genome has a regulatory function in gene expression. The technological progress made in recent years permitted the revision of old and discovery of new mutations outside of the protein-coding regions that do affect human limb morphology. Steadily increasing discovery rate of such mutations suggests that until now the largely neglected part of the genome rises to its well-deserved prominence. In this review, we describe the recent technological advances permitting this unprecedented advance in identifying non-coding mutations. We especially focus on the mutations in cis-regulatory elements such as enhancers, and trans-regulatory elements such as miRNA and long non-coding RNA, linked to hereditary or inborn limb defects. We also discuss the role of chromatin organisation and enhancer–promoter interactions in the aetiology of limb malformations.

scholarly journals An open resource of structural variation for medical and population genetics

2019 ◽  
Author(s):  
Ryan L. Collins ◽  
Harrison Brand ◽  
Konrad J. Karczewski ◽  
Xuefang Zhao ◽  
Jessica Alföldi ◽  
...  
Keyword(s):  
Population Genetics ◽  
Large Scale ◽  
Association Studies ◽  
Point Mutations ◽  
Regulatory Elements ◽  
Disease Association ◽  
Clinical Genetic ◽  
High Coverage ◽  
Protein Coding ◽  
Clinical Genetic Testing

SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.

scholarly journals A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus

2020 ◽  
Author(s):  
BE Aronson ◽  
L Scourzic ◽  
V Shah ◽  
E Swanzey ◽  
A Kloetgen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cpg Island ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Control Element ◽  
List Type ◽  
Allele Specific ◽  
Functional Hierarchy ◽  
Functional Components

SUMMARYDysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternal Gtl2 lncRNA by precluding de novo DNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entire Dlk1-Dio3 locus. Although the targeted repression of either IG-DMR or Gtl2 promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control of Dlk1-Dio3 imprinting by allele-specific restriction of the DNA (de)methylation machinery.HIGHLIGHTSThe IG-DMR is a bipartite element with distinct allele-specific functionsA non-canonical enhancer within the IG-DMR prevents DNA methyltransferase activityTargeted epigenome editing allows induction of specific imprinting phenotypesCRISPRi reveals a functional hierarchy between DMRs that dictates imprint stability

scholarly journals Independent recruitment of PRC1 and PRC2 by human XIST

2020 ◽  
Author(s):  
Thomas Dixon-McDougall ◽  
Carolyn J. Brown
Keyword(s):  
Large Scale ◽  
Chromatin Modification ◽  
Protein Coding ◽  
X Chromosomes ◽  
Non Coding Rna ◽  
Exciting Potential ◽  
Multiple Regions ◽  
Protein Recruitment ◽  
The Impact ◽  
Large Sections

AbstractXIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. PRC1 recruitment required four distinct regions of XIST, and these were completely distinct from the two domains crucial for PRC2 recruitment. Both the domains required and the impact of inhibitors suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates a role for additional factors. The independence of the PRC1/PRC2 pathways, yet important of all regions tested, demonstrate both modularity and cooperativity across the XIST lncRNA.Author SummaryXIST functions as a long, non-protein coding, RNA to initiate various pathways for the silencing of one of the two X chromosomes in female placental mammals. CRISPR-directed mutations of an inducible human XIST construct in somatic cells allowed us to discover which regions of the RNA are required for chromatin modification and protein recruitment. This was the first large-scale dissection of human XIST domains, and every function assessed was dependent on multiple regions of XIST, suggesting considerable interactions between domains of XIST. We observed similarities, but also differences, with the domains previously identified in mouse Xist and demonstrated the presence of independent pathways for chromosome reorganization in humans as well as ascribing new functionality to regions of XIST. The ability of XIST to inactivate large sections of chromosomes from which it is expressed makes it both an exciting potential therapeutic for chromosome number abnormalities as well as a paradigm for how non-coding RNA genes are able to regulate cellular biology.

scholarly journals Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3062-3071 ◽  
Author(s):  
Qian Zhang ◽  
HongYi Wang ◽  
Kanchan Kantekure ◽  
Jennifer C. Paterson ◽  
Xiaobin Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cell ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Transcriptional Activity ◽  
Cell Lymphoma ◽  
Cpg Island ◽  
Methylation Status ◽  
T Cell Lymphoma ◽  
Growth Promoting

Abstract Here we report that T-cell lymphoma cells carrying the NPM-ALK fusion protein (ALK+ TCL) frequently express the cell-stimulatory receptor ICOS. ICOS expression in ALK+ TCL is moderate and strictly dependent on the expression and enzymatic activity of NPM-ALK. NPM-ALK induces ICOS expression via STAT3, which triggers the transcriptional activity of the ICOS gene promoter. In addition, STAT3 suppresses the expression of miR-219 that, in turn, selectively inhibits ICOS expression. ALK+ TCL cell lines display extensive DNA methylation of the CpG island located within intron 1, the putative enhancer region, of the ICOS gene, whereas cutaneous T-cell lymphoma cell lines, which strongly express ICOS, show no methylation of the island. Treatment of the ALK+ TCL cell lines with DNA methyltransferase inhibitor reversed the CpG island methylation and augmented the expression of ICOS mRNA and protein. Stimulation of the ICOS receptor with anti-ICOS antibody or ICOS ligand-expressing B cells markedly enhanced proliferation of the ALK+ TCL cells. These results demonstrate that NPM-ALK, acting through STAT3 as the gene transcriptional activator, induces the expression of ICOS, a cell growth promoting receptor. These data also show that the DNA methylation status of the intronic CpG island affects transcriptional activity of the ICOS gene and, consequently, modulates the concentration of the expressed ICOS protein.

scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

scholarly journals Classifying gastric cancer using FLORA reveals clinically relevant molecular subtypes and highlights LINC01614 as a biomarker for patient prognosis

Oncogene ◽  
2021 ◽  
Author(s):  
Yiyun Chen ◽  
Wing Yin Cheng ◽  
Hongyu Shi ◽  
Shengshuo Huang ◽  
Huarong Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Noncoding Rna ◽  
Molecular Subtype ◽  
Sequencing Data ◽  
Cell Growth And Migration ◽  
Protein Coding ◽  
Over Expression ◽  
And Migration ◽  
Patient Prognosis ◽  
Subtype 3

AbstractMolecular-based classifications of gastric cancer (GC) were recently proposed, but few of them robustly predict clinical outcomes. While mutation and expression signature of protein-coding genes were used in previous molecular subtyping methods, the noncoding genome in GC remains largely unexplored. Here, we developed the fast long-noncoding RNA analysis (FLORA) method to study RNA sequencing data of GC cases, and prioritized tumor-specific long-noncoding RNAs (lncRNAs) by integrating clinical and multi-omic data. We uncovered 1235 tumor-specific lncRNAs, based on which three subtypes were identified. The lncRNA-based subtype 3 (L3) represented a subgroup of intestinal GC with worse survival, characterized by prevalent TP53 mutations, chromatin instability, hypomethylation, and over-expression of oncogenic lncRNAs. In contrast, the lncRNA-based subtype 1 (L1) has the best survival outcome, while LINC01614 expression further segregated a subgroup of L1 cases with worse survival and increased chance of developing distal metastasis. We demonstrated that LINC01614 over-expression is an independent prognostic factor in L1 and network-based functional prediction implicated its relevance to cell migration. Over-expression and CRISPR-Cas9-guided knockout experiments further validated the functions of LINC01614 in promoting GC cell growth and migration. Altogether, we proposed a lncRNA-based molecular subtype of GC that robustly predicts patient survival and validated LINC01614 as an oncogenic lncRNA that promotes GC proliferation and migration.

scholarly journals Small Non-Coding-RNA in Gynecological Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1085
Author(s):  
Shailendra Kumar Dhar Dwivedi ◽  
Geeta Rao ◽  
Anindya Dey ◽  
Priyabrata Mukherjee ◽  
Jonathan D. Wren ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
P Element ◽  
Gynecologic Malignancies ◽  
Diagnosis And Prognosis ◽  
Gynecological Malignancies ◽  
Non Coding Rna ◽  
Therapeutic Research ◽  
Regulatory Functions

Gynecologic malignancies, which include cancers of the cervix, ovary, uterus, vulva, vagina, and fallopian tube, are among the leading causes of female mortality worldwide, with the most prevalent being endometrial, ovarian, and cervical cancer. Gynecologic malignancies are complex, heterogeneous diseases, and despite extensive research efforts, the molecular mechanisms underlying their development and pathology remain largely unclear. Currently, mechanistic and therapeutic research in cancer is largely focused on protein targets that are encoded by about 1% of the human genome. Our current understanding of 99% of the genome, which includes noncoding RNA, is limited. The discovery of tens of thousands of noncoding RNAs (ncRNAs), possessing either structural or regulatory functions, has fundamentally altered our understanding of genetics, physiology, pathophysiology, and disease treatment as they relate to gynecologic malignancies. In recent years, it has become clear that ncRNAs are relatively stable, and can serve as biomarkers for cancer diagnosis and prognosis, as well as guide therapy choices. Here we discuss the role of small non-coding RNAs, i.e., microRNAs (miRs), P-Element induced wimpy testis interacting (PIWI) RNAs (piRNAs), and tRNA-derived small RNAs in gynecological malignancies, specifically focusing on ovarian, endometrial, and cervical cancer.

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