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RNA-Seq characterization of select lincRNA knockout mouse models

ABSTRACT: It has become clear that long intergenic noncoding RNAs (lincRNAs) are an important layer of genome regulation. Thousands have been identified in mammals, yet only a few have been tested through genetic ablation in animal models. Of the few that have, many yields weak to unobservable phenotypes, raising the question of their in vivo relevance. To more broadly investigate the functional relevance of lincRNAs in physiological conditions, we developed a collection of 18 lincRNA knockout strains. We found that two knockout strains, linc-Sox2 and linc-Foxf1a (Fendrr), exhibit perinatal lethal phenotypes in addition to multiple developmental abnormalities. Notably, in depth analysis of a third mutant strain, linc-Brn1b-/-, revealed defects in brain development, with distinct abnormalities in class-specific generation of upper layer II/III-IV neurons in the neocortex. Thus far, we found at least 6 of 18 mutant strains exhibit distinct developmental or lethality phenotypes. Therefore, this study demonstrates that lincRNAs are required for life and play critical roles during mammalian development, highlighting the importance of studying them further to better understand the molecular mechanisms leading to disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE49581 | GEO | 2013/11/30

SECONDARY ACCESSION(S): PRJNA214363

REPOSITORIES: GEO

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RNA-Seq characterization of select lincRNA knockout mouse models

Project description:It has become clear that long intergenic noncoding RNAs (lincRNAs) are an important layer of genome regulation. Thousands have been identified in mammals, yet only a few have been tested through genetic ablation in animal models. Of the few that have, many yields weak to unobservable phenotypes, raising the question of their in vivo relevance. To more broadly investigate the functional relevance of lincRNAs in physiological conditions, we developed a collection of 18 lincRNA knockout strains. We found that two knockout strains, linc-Sox2 and linc-Foxf1a (Fendrr), exhibit perinatal lethal phenotypes in addition to multiple developmental abnormalities. Notably, in depth analysis of a third mutant strain, linc-Brn1b-/-, revealed defects in brain development, with distinct abnormalities in class-specific generation of upper layer II/III-IV neurons in the neocortex. Thus far, we found at least 6 of 18 mutant strains exhibit distinct developmental or lethality phenotypes. Therefore, this study demonstrates that lincRNAs are required for life and play critical roles during mammalian development, highlighting the importance of studying them further to better understand the molecular mechanisms leading to disease. Minimum 2 replicates each of select wild type and lincRNA knockout embryonic and postnatal tissues for three distinct lincRNA knockout mouse strains.

2013-11-30 | E-GEOD-49581 | biostudies-arrayexpress

Systematic evaluation of C. elegans lincRNAs with CRISPR knockout mutants [ChIP-Seq]

Project description:Background: LincRNAs play critical roles in eukaryotic cells, but systematic analyses of lincRNAs of an animal for phenotypes have been missing. We have generated CRISPR knockout strains for C. elegans lincRNAs and have evaluated their phenotypes Results: C. elegans lincRNAs demonstrate global features such as shorter length and fewer exons than mRNAs. For the systematic evaluation of C. elegans lincRNAs, CRISPR knockout strains for 155 out of all the 170 C. elegans lincRNAs were produced. Mutants of 23 lincRNAs have shown phenotypes in 6 traits analyzed. We have investigated these phenotypic lincRNAs for their gene expression patterns and their potential functional mechanisms. Some C. elegans lincRNAs play cis roles to modulate the expression of their neighboring genes, and some other lincRNAs play trans roles as ceRNAs against microRNAs. LincRNAs are extensively regulated by transcription factors, and we dissect the pathway that two transcription factors UNC-30 and UNC-55 control the expression of linc-73 together. Furthermore, linc-73 plays a cis role to modulate the expression of its neighboring gene unc-104, and thus regulates the formation of presynapses. Conclusions: By using CRISPR/cas9 technology, we have generated knockout strains of 155 C. elegans lincRNAs as valuable resources for studies in noncoding RNAs, and we provide biological insights for 23 phenotypic lincRNAs identified from 6 traits examined.

2018-12-27 | GSE122973 | GEO

Systematic evaluation of C. elegans lincRNAs with CRISPR knockout mutants [miRNA-seq]

2018-12-27 | GSE115321 | GEO

Systematic evaluation of C. elegans lincRNAs with CRISPR knockout mutants [lncRNA-seq]

2018-12-27 | GSE115320 | GEO

Systematic Analysis of Long Intergenic Non-Coding RNAs in C. elegans Germline Uncovers Roles in Somatic Growth

Project description:Long intergenic non-coding RNAs (lincRNAs) are transcripts longer than 200 nucleotides that are transcribed from non-coding loci yet undergo biosynthesis similar to coding mRNAs. The disproportional number of lincRNAs expressed in testes suggests that lincRNAs are important during gametogenesis, but experimental evidence has implicated very few lincRNAs in this process. We took advantage of the relatively limited number of lincRNAs in the genome of the nematode Caenorhabditis elegans to systematically analyse the functions of lincRNAs during meiosis. We deleted six lincRNA genes that are highly and dynamically expressed in the C. elegans gonad and tested the effects on central meiotic processes. Surprisingly, whereas the lincRNA deletions did not strongly impact fertility, germline apoptosis, crossovers, or synapsis, linc-4 was required for somatic growth. Slower growth was observed in linc-4-deletion mutants and in worms depleted of linc-4 using RNAi, indicating that linc-4 transcripts are required for this post-embryonic process. Unexpectedly, analysis of worms depleted of linc-4 in soma versus germline showed that the somatic role stems from linc-4 expression in germline cells. This unique feature suggests that some lincRNAs, like some small non-coding RNAs, are required for germ-soma interactions

2021-07-31 | GSE154322 | GEO

Six homeoproteins and a linc-RNA cooperate at the fast MYH locus to lock terminal fast myofibre phenotype

Project description:Thousands of long intergenic noncoding RNAs (lincRNAs) are encoded by the mammalian genome, which were reported to have multiple biological functions as transcriptional activators acting in cis 1 or trans 2, transcriptional repressors 3,4 or miRNAs decoys 5,6. However, the function of most lincRNAs has not yet been identified in vivo. Here, we demonstrate a role for linc-MYH, a novel long intergenic noncoding RNA, in adult fast-type myofibre specialization. Skeletal myofibre fast and slow phenotypes are established through differential expression of numerous fibre-specific genes7. We show linc-MYH and the fast MYH genes share a common enhancer located in the fast MYH genes locus and regulated by the Six1 homeoproteins. Muscle-specific Six1 mutant mice show increased expression of slow-type genes, and downregulation of linc-MYH and fast-type genes. linc-MYH function revealed by in vivo knockdown and wide transcriptomic analysis, is in fine to prevent expression of genes ensuring slow muscle contractile properties, and to increase fast-type muscle gene expression in fast-type myofibres. Thus, formation of efficient fast sarcomeric units and appropriate Ca++ cycling and excitation/contraction/relaxation coupling in fast- myofibres is achieved through the coordiante control of fast MYHs and linc-MYH expression by a Six bound enhancer.

2014-04-27 | GSE46151 | GEO

Human Long Intergenic Noncoding RNA Linc-ADAL Knockdown in Mature Adipocytes using Lentiviral ShRNA

Project description:Thousands of human long intergenic noncoding RNAs (lincRNAs) have been detected in human adipose tissue. Here we characterized the function of one human adipse lincRNA, linc-ADAL (chr5:115292235-115296985) in mature adipcoytes through loss-of-function studies. Our results indicate that knockdown of linc-ADAL in differentiated adipocytes modulated expression of lipid metabolism genes.

2019-02-13 | GSE95173 | GEO

Transcriptome Analysis Identifies Linc-Yy1, A Novel Functional LincRNA During Myogenesis

Project description:Little is known how lincRNAs are involved in skeletal myogenesis. Here we describe the discovery of a novel lincRNA, Linc-YY1 from the promoter of transcription factor (TF) Yin Yang 1 (YY1) gene. We demonstrate that Linc-YY1 is dynamically regulated during myogenesis in vitro and in vivo. Gain or loss of function of Linc-YY1 in C2C12 myoblast cells or satellite cells alters myogenic differentiation and in injured muscles impacts the course of regeneration. Further studies suggest LincYY1 may interact with YY1 through its middle domain to evict YY1

2015-10-16 | GSE74049 | GEO

Trans-chromosomal regulation by a novel lincRNA required for adipogenesis that escapes X-chromosome inactivation

Project description:Long noncoding RNAs (lncRNAs) have emerged as an important layer of genome regulation with common mechanistic themes including the formation of ribonucleoprotein complexes. Here, we present a novel X-linked lncRNA termed linc-Firre that escapes X-chromosome inactivation and forms trans-chromosomal interactions required for adipogenesis. Linc-Firre is exclusively nuclear and forms punctate expression foci on chromatin near its site of transcription on both X-chromosomes in human and mouse. Both the localization of linc-Firre and the association with the nuclear matrix protein hnRNPU require a conserved repeating RNA domain, R2D2. Collectively, these results reveal a lincRNA that escapes X-chromosome inactivation with a critical role in driving cell fate decisions by trans-chromosomal interactions. Replicate RNA-Seq analyses of oligo-mediated knockdowns of linc-FIRRE and hnRNPU in two different cellular contexts; HeLa cells and mouse embryonic stem cells.

2013-06-01 | E-GEOD-45157 | biostudies-arrayexpress

Linc-ADAIN, A Human Adipose LincRNA Regulates Adipogenesis by Modulating KLF5 and IL-8 mRNA stability

Project description:Adipose tissue remodeling and dysfunction, characterized by increased inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2DM) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here we describe the functions of linc-ADAIN (ADipose Anti-INflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans. We demonstrate that linc-ADAIN knockdown (KD) increases KLF5 and IL-8 mRNA stability and translation, by interacting with IGF2BP2. Upregulation of KLF5 and IL-8, via linc-ADAIN KD, led to an enhanced adipogenic program and adipose tissue inflammation, mirroring the obese state, in vitro and in vivo, KD of linc-ADAIN in human ASC hTERT adipocytes implanted into mice, increased adipocyte size and macrophage infiltration compared to implanted control adipocytes, mimicking hallmark features of obesity-induced adipose tissue remodeling. Linc-ADAIN is an anti-inflammatory lincRNA that limits adipose tissue expansion and lipid storage.

2024-04-16 | GSE263852 | GEO

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