scholarly journals Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs

2017 ◽  
Author(s):  
Joana Carlevaro-Fita ◽  
Taisia Polidori ◽  
Monalisa Das ◽  
Carmen Navarro ◽  
Tatjana I. Zoller ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Types ◽  
Subcellular Localisation ◽  
Evolutionary Selection ◽  
Dependent Relationship ◽  
Evolutionarily Conserved ◽  
Show Evidence ◽  
Multiple Cell

AbstractThe sequence domains underlying long noncoding RNA (lncRNA) activities, including their characteristic nuclear enrichment, remain largely unknown. It has been proposed that these domains can originate from neofunctionalised fragments of transposable elements (TEs), otherwise known as RIDLs (Repeat Insertion Domains of Long Noncoding RNA), although just a handful have been identified. It is challenging to distinguish functional RIDL instances against a numerous genomic background of neutrally-evolving TEs. We here show evidence that a subset of TE types experience evolutionary selection in the context of lncRNA exons. Together these comprise an enrichment group of 5374 TE fragments in 3566 loci. Their host lncRNAs tend to be functionally validated and associated with disease. This RIDL group was used to explore the relationship between TEs and lncRNA subcellular localisation. Using global localisation data from ten human cell lines, we uncover a dose-dependent relationship between nuclear/cytoplasmic distribution, and evolutionarily-conserved L2b, MIRb and MIRc elements. This is observed in multiple cell types, and is unaffected by confounders of transcript length or expression. Experimental validation with engineered transgenes shows that these TEs drive nuclear enrichment in a natural sequence context. Together these data reveal a role for TEs in regulating the subcellular localisation of lncRNAs.

scholarly journals An Evolutionarily Conserved Long Noncoding RNA TUNA Controls Pluripotency and Neural Lineage Commitment

2014 ◽  
Vol 53 (6) ◽  
pp. 1005-1019 ◽  
Author(s):  
Nianwei Lin ◽  
Kung-Yen Chang ◽  
Zhonghan Li ◽  
Keith Gates ◽  
Zacharia A. Rana ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Lineage Commitment ◽  
Neural Lineage ◽  
Evolutionarily Conserved

scholarly journals Tribbles in normal and malignant haematopoiesis

2015 ◽  
Vol 43 (5) ◽  
pp. 1112-1115 ◽  
Author(s):  
Sarah J. Stein ◽  
Ethan A. Mack ◽  
Kelly S. Rome ◽  
Warren S. Pear
Keyword(s):  
E3 Ligase ◽  
Cell Types ◽  
Protein Family ◽  
Conserved Motifs ◽  
Tissue Specific ◽  
Cellular Events ◽  
Haematopoietic Cells ◽  
Evolutionarily Conserved ◽  
Multiple Cell

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.

scholarly journals An Evolutionarily Conserved Long Noncoding RNA TUNA Controls Pluripotency and Neural Lineage Commitment

2014 ◽  
Vol 53 (6) ◽  
pp. 1067 ◽  
Author(s):  
Nianwei Lin ◽  
Kung-Yen Chang ◽  
Zhonghan Li ◽  
Keith Gates ◽  
Zacharia A. Rana ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Lineage Commitment ◽  
Neural Lineage ◽  
Evolutionarily Conserved

scholarly journals Myeloid leukemia vulnerabilities at CTCF-enriched long noncoding RNA loci

2021 ◽  
Author(s):  
Michelle Ng ◽  
Lonneke Verboon ◽  
Hasan Issa ◽  
Raj Bhayadia ◽  
Oriol Alejo-Valle ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
K562 Cells ◽  
Cell Types ◽  
Clinical Aspects ◽  
Hematopoietic Stem ◽  
Regulatory Effects

Abstract The noncoding genome presents a largely untapped source of biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide lncRNAs, others exert transcript-independent cis-regulatory effects, and the lack of predictive features renders mechanistic dissection challenging. Here, we describe CTCF-enriched lncRNA loci (C-LNC) as a subclass of functional genetic elements exemplified by MYNRL15, a pan-myeloid leukemia dependency identified by an lncRNA-based CRISPRi screen. MYNRL15 perturbation selectively impairs acute myeloid leukemia (AML) cells over hematopoietic stem / progenitor cells in vitro, and depletes AML xenografts in vivo. Mechanistically, we show that crucial DNA elements in the locus mediate its phenotype, triggering chromatin reorganization and downregulation of cancer dependency genes upon perturbation. Elevated CTCF density distinguishes MYNRL15 and 531 other lncRNA loci in K562 cells, of which 43-54% associate with clinical aspects of AML and 18.4% are functionally required for leukemia maintenance. Curated C-LNC catalogs in other cell types will help refine the search for noncoding oncogenic vulnerabilities in AML and other malignancies.

scholarly journals Small Extracellular Vesicle Enrichment of a Retrotransposon-Derived Double-Stranded RNA: A Means to Avoid Autoinflammation?

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1136
Author(s):  
Marilou H. Barrios ◽  
Alexandra L. Garnham ◽  
Andrew D. Foers ◽  
Lesley Cheng-Sim ◽  
Seth L. Masters ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cell Types ◽  
Bioinformatic Analysis ◽  
Extracellular Vesicle ◽  
Interferon Response ◽  
Type I ◽  
Double Stranded Rna ◽  
Multiple Cell ◽  
Toxic Rna ◽  
Cellular Components

Small extracellular vesicles (SEVs) such as exosomes are released by multiple cell types. Originally believed to be a mechanism for selectively removing unwanted cellular components, SEVs have received increased attention in recent years for their ability to mediate intercellular communication. Apart from proteins and lipids, SEVs contain RNAs, but how RNAs are selectively loaded into SEVs remains poorly understood. To address this question, we profiled SEV RNAs from mouse dendritic cells using RNA-Seq and identified a long noncoding RNA of retroviral origin, VL30, which is highly enriched (>200-fold) in SEVs compared to parental cells. Bioinformatic analysis revealed that exosome-enriched isoforms of VL30 RNA contain a repetitive 26-nucleotide motif. This repeated motif is itself efficiently incorporated into SEVs, suggesting the likelihood that it directly promotes SEV loading. RNA folding analyses indicate that the motif is likely to form a long double-stranded RNA hairpin and, consistent with this, its overexpression was associated with induction of a potent type I interferon response. Taken together, we propose that preferential loading into SEVs of the VL30 RNA containing this immunostimulatory motif enables cells to remove a potentially toxic RNA and avoid autoinflammation. In this way, the original notion of SEVs as a cellular garbage bin should not be entirely discounted.

scholarly journals Myeloid leukemia vulnerabilities at CTCF-enriched long noncoding RNA loci

2021 ◽  
Author(s):  
Michelle Ng ◽  
Lonneke Verboon ◽  
Hasan Issa ◽  
Raj Bhayadia ◽  
Oriol Alejo-Valle ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Hematopoietic Stem ◽  
Regulatory Effects

Abstract The noncoding genome presents a largely untapped source of biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide lncRNAs, others exert transcript-independent cis-regulatory effects, and a lack of predictive features renders mechanistic dissection challenging. Here, we describe MYNRL15, a CTCF-enriched lncRNA locus and pan-myeloid leukemia dependency initially identified by expression-guided CRISPR interference screens. We show that accessibility and integrity of the MYNRL15 locus is required for myeloid leukemia maintenance; its perturbation selectively impairs acute myeloid leukemia (AML) cells compared to hematopoietic stem and progenitor cells in vitro, and depletes AML xenografts in vivo. While the MYNRL15 transcript and neighboring protein-coding genes appear dispensable, dense CRISPR tiling of the locus revealed two crucial candidate cis-regulatory DNA elements which drive the perturbation phenotype. Disruption of these elements triggers the formation of a tumor-suppressive, long-range chromatin interaction. By integrating transcriptome profiling with a CRISPR-Cas9 knockout screen of genes from the gained interaction region, we pinpointed two downregulated, potent cancer dependency genes as effectors of MYNRL15 disruption: WDR61 and IMP3. Finally, guided by distinctive features of the MYNRL15 locus, we find that elevated CTCF density characterizes a set of lncRNA loci enriched in leukemia vulnerabilities (22.6-24.2% essentiality rate). A catalog of CTCF-enriched lncRNA loci (C-LNCs) in 18 cell types representing different cancer entities and tissues is provided with this study, towards refining the search for noncoding oncogenic vulnerabilities in leukemia and other malignancies.

scholarly journals Prohibitin: A hypothetical target for sex-based new therapeutics for metabolic and immune diseases

2019 ◽  
Vol 244 (2) ◽  
pp. 157-170 ◽  
Author(s):  
Suresh Mishra ◽  
BL Grégoire Nyomba
Keyword(s):  
Sex Differences ◽  
Sex Steroids ◽  
Immune Cell ◽  
Cell Types ◽  
Immune Functions ◽  
Evolutionarily Conserved ◽  
Health And Disease ◽  
Multiple Cell ◽  
Membrane Signaling

Adipose and immune functions display sex differences and are influenced by sex steroid hormones in health and disease. However, effector molecules that mediate the effects of sex steroids and determine sex differences in adipocytes and immune cells are largely unknown. Sex differences are known to exist in mitochondrial biology, and mitochondria play a crucial role in adipocyte and immune cell functions. In fact, mitochondrial dysregulation is a common finding in a number of diseases that exhibit sex differences. It is, therefore, possible that mitochondria carry out sex-dimorphic functions. Prohibitin, an evolutionarily conserved pleiotropic protein, known to function as a mitochondrial chaperone, has multifaceted relationship with sex steroids and their receptors. New evidence indicates that prohibitin has roles in sex differences in multiple cell and tissue types, including adipocytes, macrophages, and dendritic cells. Transgenic mice overexpressing prohibitin in adipocytes, macrophages, and dendritic cells exhibit sex differences in metabolic and immune phenotypes, mediated through mitochondrial and plasma membrane signaling functions of prohibitin. Thus, the discovery of prohibitin as mediating the effects of sex steroids in multiple cell types has opened a new research direction to study the relationship between sex steroids and mitochondrial proteins and their impact on sex differences in health and disease. In this opinion article, we will provide a personal perspective of the role of prohibitin with cellular compartment- and tissue-specific functions in mediating sex-dimorphic adipose and immune functions. We believe that prohibitin is a potential target for sex-based new therapeutics for metabolic and immune diseases. Impact statement Traditional sex-related biases in research are now obsolete, and it is important to identify the sex of humans, animals, and even cells in research protocols, due to the role of sex as a fundamental facet of biology, predisposition to disease, and response to therapy. Genetic sex, epigenetics and hormonal regulations, generate sex-dimorphisms. Recent investigations acknowledge sex differences in metabolic and immune health as well as chronic diseases. Prohibitin, an evolutionarily conserved molecule, has pleotropic functions in mitochondrial housekeeping, plasma membrane signaling, and nuclear genetic transcription. Studies in adipocytes, macrophages, and transgenic mice indicate that prohibitin interacts with sex steroids and plays a role in mediating sex differences in adipose tissues and immune cell types. Prohibitin may, depending on context, modulate predisposition to chronic metabolic diseases and malignancy and, because of these attributes, could be a target for sex-based therapies of metabolic and immune-related diseases as well as cancer.

scholarly journals Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)–mediated induction of the long noncoding RNA NICI

2019 ◽  
Vol 295 (13) ◽  
pp. 4065-4078 ◽  
Author(s):  
Victoria Lauer ◽  
Steffen Grampp ◽  
James Platt ◽  
Veronique Lafleur ◽  
Olivia Lombardi ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Glucose Transporter ◽  
Glucose Consumption ◽  
Cell Types ◽  
Cell Renal Cell Carcinoma ◽  
Protein Coding ◽  
Von Hippel Lindau ◽  
Patient Prognosis

Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long noncoding RNA Noncoding Intergenic Co-Induced transcript (NICI) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knockdown or knockout of NICI attenuated hypoxic induction of SLC2A3, indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR–mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than posttranscriptional mechanisms because knockout of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the von Hippel–Lindau (VHL) tumor suppressor and is highly expressed in clear cell renal cell carcinoma (ccRCC), where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.

scholarly journals Forced isoform switching of Neat1_1 to Neat1_2 leads to the loss of Neat1_1 and the hyperformation of paraspeckles but does not affect the development and growth of mice

2019 ◽  
Author(s):  
Momo Isobe ◽  
Hikaru Toya ◽  
Mari Mito ◽  
Tomoki Chiba ◽  
Hiroshi Asahara ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Gene Locus ◽  
Cell Types ◽  
Small Population ◽  
Nuclear Bodies ◽  
Mutant Mice ◽  
Isoform Switching ◽  
Tip Cells ◽  
Normal Laboratory

AbstractNeat1 is a long noncoding RNA (lncRNA) that serves as an architectural component of the nuclear bodies known as paraspeckles. Two isoforms of Neat1, the short isoform Neat1_1 and the long isoform Neat1_2, are generated from the same gene locus by alternative 3’ processing. Neat1_1 is the most abundant and the best conserved isoform expressed in various cell types, whereas Neat1_2 is expressed in a small population of particular cell types, including the tip cells of the intestinal epithelium. To investigate the physiological significance of isoform switching, we created mutant mice that solely expressed Neat1_2 by deleting the upstream polyadenylation (poly-A) signal (PAS) required for the production of Neat1_1. We observed the loss of Neat1_1 and strong upregulation of Neat1_2 in various tissues and cells and the subsequent hyperformation of paraspeckles, especially in cells that normally express Neat1_2. However, the mutant mice were born at the expected Mendelian ratios and did not exhibit obvious external and histological abnormalities. These observations suggested that the hyperformation of paraspeckles does not interfere with the development and growth of these animals under normal laboratory conditions.

scholarly journals Patterns of microsatellite distribution reflect the evolution of biological complexity

2018 ◽  
Author(s):  
Surabhi Srivastava ◽  
Akshay Kumar Avvaru ◽  
Divya Tej Sowpati ◽  
Rakesh K Mishra
Keyword(s):  
Related Species ◽  
Cell Types ◽  
Model Organisms ◽  
Closely Related Species ◽  
Repeat Elements ◽  
Evolutionary Selection ◽  
Coding Regions ◽  
Evolutionarily Conserved ◽  
Species Specific ◽  
Multicellular Organisms

AbstractMicrosatellites, also known as Simple Sequence Repeats (SSRs), are evolutionarily conserved repeat elements distributed non-randomly in all genomes. Many studies have investigated their pattern of occurrence in order to understand their role, but their identification has largely been non-exhaustive and limited to a few related species or model organisms. Here, we identify ~685 million microsatellites from 719 eukaryotes and analyze their evolutionary trends from protists to mammals. We document novel patterns uniquely demarcating closely related species, including in pathogens like Leishmania as well as in higher organisms such as Drosophila, birds, primates, and cereal crops. The distribution of SSRs in coding and non-coding regions reveals taxon-specific variations in their exonic, intronic and intergenic densities. We also show that specific SSRs accumulate at longer lengths in higher organisms indicating an evolutionary selection pressure. In general, we observe greater constraints in the SSR composition of multicellular organisms with complex cell types, while simpler organisms show more diversity. The conserved microsatellite trends and species-specific signatures identified in this study closely mirror phylogenetic relationships and we hypothesize that SSRs are integral components in speciation and the evolution of organismal complexity. The microsatellite dataset generated in this work provides a large number of candidates for functional analysis and unparalleled scope for understanding their roles across the evolutionary landscape.

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