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A multifunctional locus controls motor neuron differentiation through short and long noncoding RNAs.

ABSTRACT: The transition from dividing progenitors to postmitotic motor neurons (MNs) is orchestrated by a series of events, which are mainly studied at the transcriptional level by analyzing the activity of specific programming transcription factors. Here, we identify a post-transcriptional role of a MN-specific transcriptional unit (MN2) harboring a lncRNA (lncMN2-203) and two miRNAs (miR-325-3p and miR-384-5p) in this transition. Through the use of in vitro mESC differentiation and single-cell sequencing of CRISPR/Cas9 mutants, we demonstrate that lncMN2-203 affects MN differentiation by sponging miR-466i-5p and upregulating its targets, including several factors involved in neuronal differentiation and function. In parallel, miR-325-3p and miR-384-5p, co-transcribed with lncMN2-203, act by repressing proliferation-related factors. These findings indicate the functional relevance of the MN2 locus and exemplify additional layers of specificity regulation in MN differentiation.

SUBMITTER: Carvelli A

PROVIDER: S-EPMC9251839 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A multifunctional locus controls motor neuron differentiation through short and long non coding RNAs

Project description:The transition from dividing progenitors to post-mitotic motor neurons (MNs) is orchestrated by a series of events, which are mainly studied at the transcriptional level by analyzing the activity of specific programming transcription factors. Here, we identify a post-transcriptional role of a MN-specific transcriptional unit (MN2) harboring a lncRNA (lncMN2-203) and two miRNAs (miR-325-3p and miR-384-5p) in this transition. Through the use of in vitro mESC differentiation and single-cell sequencing of CRISPR/Cas9 mutants, we demonstrate that lncMN2-203 affects MN differentiation by sponging miR-466i-5p and up-regulating its targets, including several factors involved in neuronal differentiation and function. In parallel, miR-325-3p and miR-384-5p, co-transcribed with lncMN2-203, act by repressing proliferation-related factors. These findings indicate the functional relevance of the MN2 locus and exemplify additional layers of specificity regulation in MN differentiation.

| S-SCDT-EMBOJ-2021-108918 | biostudies-other

A multifunctional locus controls motor neuron differentiation through short and long non coding RNAs

Project description:The transition from dividing progenitors into post-mitotic motor neurons is orchestrated by a series of events mainly studied at the transcriptional level by analyzing the activity of specific programming transcription factors. In this work, we describe that a motor neuron-specific transcriptional unit, harboring a lncRNA (lncMN2-203) and two miRNAs (miR-325-3p and miR-384-5p), controls such transition at the post-transcriptional level. Through the use of in vitro differentiation of mESC and single-cell sequencing of CRISPR/Cas9 mutants, we demonstrate that lncMN2-203 affects motor neuron differentiation by sponging miR-466i-5p and up-regulating its targets; among them Onecut2, which is the upstream regulator of the MN-specific programming factor Islet-1. In synergy with lncMN2-203, instead the depletion of the co-transcribed miR-325-3p and miR-384-5p was found to mainly sustain proliferation-related factors. These findings indicate the functional relevance of the MN2 locus and contribute to elucidate additional layers of regulation controlling the specificity of motor neuron differentiation.

2021-11-16 | GSE174671 | GEO

A multifunctional locus controls motor neuron differentiation through short and long non coding RNAs

Project description:A multifunctional locus controls motor neuron differentiation through short and long non coding RNAs

| PRJNA731036 | ENA

A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture.

Project description:Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers.

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Making a long story short: noncoding RNAs and chromosome change.

Project description:As important as the events that influence selection for specific chromosome types in the derivation of novel karyotypes, are the events that initiate the changes in chromosome number and structure between species, and likewise polymorphisms, variants and disease states within species. Although once thought of as transcriptional 'noise', noncoding RNAs (ncRNAs) are now recognized as important mediators of epigenetic regulation and chromosome stability. Here we highlight recent work that illustrates the influence short and long ncRNAs have as participants in the function and stability of chromosome regions such as centromeres, telomeres, evolutionary breakpoints and fragile sites. We summarize recent evidence that ncRNAs can facilitate chromosome change and present mechanisms by which ncRNAs create DNA breaks. Finally, we present hypotheses on how they may create novel karyotypes and thus affect chromosome evolution.

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Novel long noncoding RNAs (lncRNAs) in myogenesis: a miR-31 overlapping lncRNA transcript controls myoblast differentiation.

Project description:Transcriptome analysis allowed the identification of new long noncoding RNAs differentially expressed during murine myoblast differentiation. These transcripts were classified on the basis of their expression under proliferating versus differentiated conditions, muscle-restricted activation, and subcellular localization. Several species displayed preferential expression in dystrophic (mdx) versus wild-type muscles, indicating their possible link with regenerative processes. One of the identified transcripts, lnc-31, even if originating from the same nuclear precursor of miR-31, is produced by a pathway mutually exclusive. We show that lnc-31 and its human homologue hsa-lnc-31 are expressed in proliferating myoblasts, where they counteract differentiation. In line with this, both species are more abundant in mdx muscles and in human Duchenne muscular dystrophy (DMD) myoblasts, than in their normal counterparts. Altogether, these data suggest a crucial role for lnc-31 in controlling the differentiation commitment of precursor myoblasts and indicate that its function is maintained in evolution despite the poor sequence conservation with the human counterpart.

| S-EPMC4301723 | biostudies-literature

Identification of long noncoding RNAs involved in muscle differentiation.

Project description:Long noncoding RNAs (lncRNAs) are a large class of regulatory RNAs with diverse roles in cellular processes. Thousands of lncRNAs have been discovered; however, their roles in the regulation of muscle differentiation are unclear because no comprehensive analysis of lncRNAs during this process has been performed. In the present study, by combining diverse RNA sequencing datasets obtained from public database, we discovered lncRNAs that could behave as regulators in the differentiation of smooth or skeletal muscle cells. These analyses confirmed the roles of previously reported lncRNAs in this process. Moreover, we discovered dozens of novel lncRNAs whose expression patterns suggested their possible involvement in the phenotypic switch of vascular smooth muscle cells. The comparison of lncRNA expression change suggested that many lncRNAs have common roles during the differentiation of smooth and skeletal muscles, while some lncRNAs may have opposite roles in this process. The expression change of lncRNAs was highly correlated with that of their neighboring genes, suggesting that they may function as cis-acting lncRNAs. Furthermore, within the lncRNA sequences, there were binding sites for miRNAs with expression levels inversely correlated with the expression of corresponding lncRNAs during differentiation, suggesting a possible role of these lncRNAs as competing endogenous RNAs. The lncRNAs identified in this study will be a useful resource for future studies of gene regulation during muscle differentiation.

| S-EPMC5834194 | biostudies-literature

Long noncoding RNAs, emerging players in muscle differentiation and disease.

Project description:The vast majority of the mammalian genome is transcribed giving rise to many different types of noncoding RNAs. Among them, long noncoding RNAs are the most numerous and functionally versatile class. Indeed, the lncRNA repertoire might be as rich as the proteome. LncRNAs have emerged as key regulators of gene expression at multiple levels. They play important roles in the regulation of development, differentiation and maintenance of cell identity and they also contribute to disease. In this review, we present recent advances in the biology of lncRNAs in muscle development and differentiation. We will also discuss the contribution of lncRNAs to muscle disease with a particular focus on Duchenne and facioscapulohumeral muscular dystrophies.

| S-EPMC3973619 | biostudies-literature

Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.

Project description:The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.

| S-EPMC2527704 | biostudies-literature

Decoding Noncoding RNAs: Role of MicroRNAs and Long Noncoding RNAs in Ocular Neovascularization.

Project description:Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization.

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