ZFP207 controls pluripotency by multiple post-transcriptional mechanisms

AbstractThe pluripotent state is not solely governed by the action of the core transcription factors Oct4, Sox2, and Nanog, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize the role of ZFP207 in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, ZFP207 does not transcriptionally regulate stem cell and neuronal-related genes but exerts its effects by control AS networks and acting as an RBP. Our study expands the role of ZFP207 to maintain ESC identity, and underscores ZFP207 functional versatility with key roles in neural fate commitment.

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Function of Pumilio Genes in Human Embryonic Stem Cells and Their Effect in Stemness and Cardiomyogenesis

10.1101/751537 ◽

2019 ◽

Author(s):

Isabelle Leticia Zaboroski Silva ◽

Anny Waloski Robert ◽

Guillermo Cabrera Cabo ◽

Lucia Spangenberg ◽

Marco Augusto Stimamiglio ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Rna Binding ◽

Rna Binding Proteins ◽

Embryonic Stem ◽

Mrna Levels ◽

Human Escs ◽

Mrna Targets ◽

Cardiomyogenic Differentiation

AbstractPosttranscriptional regulation plays a fundamental role in the biology of embryonic stem cells (ESCs). Many studies have demonstrated that multiple mRNAs are coregulated by one or more RNA binding proteins (RBPs) that orchestrate the expression of these molecules. A family of RBPs, known as PUF (Pumilio-FBF), is highly conserved among species and has been associated with the undifferentiated and differentiated states of different cell lines. In humans, two homologs of the PUF family have been found: Pumilio 1 (PUM1) and Pumilio 2 (PUM2). To understand the role of these proteins in human ESCs (hESCs), we first demonstrated the influence of the silencing of PUM1 and PUM2 on pluripotency genes. OCT4 and NANOG mRNA levels decreased significantly with the knockdown of Pumilio, suggesting that PUMILIO proteins play a role in the maintenance of pluripotency in hESCs. Furthermore, we observed that the hESCs silenced for PUM1 and 2 exhibited an improvement in efficiency of in vitro cardiomyogenic differentiation. Using in silico analysis, we identified mRNA targets of PUM1 and PUM2 expressed during cardiomyogenesis. With the reduction of PUM1 and 2, these target mRNAs would be active and could be involved in the progression of cardiomyogenesis.

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The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

Current Gene Therapy ◽

10.2174/1566523219666190716092203 ◽

2019 ◽

Vol 19 (4) ◽

pp. 255-263 ◽

Cited By ~ 13

Author(s):

Yuangang Wu ◽

Xiaoxi Lu ◽

Bin Shen ◽

Yi Zeng

Keyword(s):

Gene Expression ◽

Gene Therapy ◽

Extracellular Matrix ◽

Inflammatory Reaction ◽

Noncoding Rna ◽

Rna Binding ◽

Rna Binding Proteins ◽

Protein Translation ◽

Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

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Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

Cell & Bioscience ◽

10.1186/s13578-021-00661-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xuechai Chen ◽

Jianan Wang ◽

Muhammad Tahir ◽

Fangfang Zhang ◽

Yuanyuan Ran ◽

...

Keyword(s):

Intervertebral Disc Degeneration ◽

Rna Binding ◽

Rna Binding Proteins ◽

Degradation Process ◽

Human Diseases ◽

Rna Modification ◽

Rna Methylation ◽

M6a Rna Methylation ◽

The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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DT-03-02: Viewing neurodegeneration beyond the tangle: The role of RNA binding proteins in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.08.014 ◽

2013 ◽

Vol 9 ◽

pp. P847-P847

Author(s):

Benjamin Wolozin ◽

Tara Vanderweyde ◽

Liqun Liu-Yesucevitz ◽

Alpaslan Dedeoglu ◽

Leonard Petrucelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins

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Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4

Biochemical Journal ◽

10.1042/bj20031176 ◽

2004 ◽

Vol 379 (2) ◽

pp. 283-289 ◽

Cited By ~ 47

Author(s):

Marie-Chloé BOULANGER ◽

Tina Branscombe MIRANDA ◽

Steven CLARKE ◽

Marco di FRUSCIO ◽

Beat SUTER ◽

...

Keyword(s):

Rna Binding ◽

Developmental Stages ◽

Rna Binding Proteins ◽

Genetic System ◽

Arginine Methylation ◽

Type I ◽

Protein Arginine Methyltransferases ◽

Arginine Residues ◽

Drosophila Protein

The role of arginine methylation in Drosophila melanogaster is unknown. We identified a family of nine PRMTs (protein arginine methyltransferases) by sequence homology with mammalian arginine methyltransferases, which we have named DART1 to DART9 (Drosophilaarginine methyltransferases 1–9). In keeping with the mammalian PRMT nomenclature, DART1, DART4, DART5 and DART7 are the putative homologues of PRMT1, PRMT4, PRMT5 and PRMT7. Other DART family members have a closer resemblance to PRMT1, but do not have identifiable homologues. All nine genes are expressed in Drosophila at various developmental stages. DART1 and DART4 have arginine methyltransferase activity towards substrates, including histones and RNA-binding proteins. Amino acid analysis of the methylated arginine residues confirmed that both DART1 and DART4 catalyse the formation of asymmetrical dimethylated arginine residues and they are type I arginine methyltransferases. The presence of PRMTs in D. melanogaster suggest that flies are a suitable genetic system to study arginine methylation.

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FUS driven circCNOT6L biogenesis in mouse and human spermatozoa supports zygote development

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-04054-8 ◽

2021 ◽

Author(s):

Teresa Chioccarelli ◽

Geppino Falco ◽

Donato Cappetta ◽

Antonella De Angelis ◽

Luca Roberto ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Rna Binding ◽

Cannabinoid Receptor ◽

Rna Binding Proteins ◽

Embryonic Stem ◽

Circular Rna ◽

Physical Interaction ◽

Knock Out ◽

Maternal Contribution ◽

Zygote Development

AbstractCircular RNA (circRNA) biogenesis requires a backsplicing reaction, promoted by inverted repeats in cis-flanking sequences and trans factors, such as RNA-binding proteins (RBPs). Among these, FUS plays a key role. During spermatogenesis and sperm maturation along the epididymis such a molecular mechanism has been poorly explored. With this in mind, we chose circCNOT6L as a study case and wild-type (WT) as well as cannabinoid receptor type-1 knock-out (Cb1−/−) male mice as animal models to analyze backsplicing mechanisms. Our results suggest that spermatozoa (SPZ) have an endogenous skill to circularize mRNAs, choosing FUS as modulator of backsplicing and under CB1 stimulation. A physical interaction between FUS and CNOT6L as well as a cooperation among FUS, RNA Polymerase II (RNApol2) and Quaking (QKI) take place in SPZ. Finally, to gain insight into FUS involvement in circCNOT6L biogenesis, FUS expression was reduced through RNA interference approach. Paternal transmission of FUS and CNOT6L to oocytes during fertilization was then assessed by using murine unfertilized oocytes (NF), one-cell zygotes (F) and murine oocytes undergoing parthenogenetic activation (PA) to exclude a maternal contribution. The role of circCNOT6L as an active regulator of zygote transition toward the 2-cell-like state was suggested using the Embryonic Stem Cell (ESC) system. Intriguingly, human SPZ exactly mirror murine SPZ.

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Systematic discovery of endogenous human ribonucleoprotein complexes

10.1101/480061 ◽

2018 ◽

Cited By ~ 2

Author(s):

Anna L. Mallam ◽

Wisath Sae-Lee ◽

Jeffrey M. Schaub ◽

Fan Tu ◽

Anna Battenhouse ◽

...

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Protein Complexes ◽

Embryonic Stem ◽

Human Protein ◽

Disease States ◽

Ribonucleoprotein Complexes ◽

Associated Proteins ◽

Domains Of Life ◽

Factor C

AbstractRNA-binding proteins (RBPs) play essential roles in biology and are frequently associated with human disease. While recent studies have systematically identified individual RBPs, their higher order assembly intoRibonucleoprotein (RNP) complexes has not been systematically investigated. Here, we describe a proteomics method for systematic identification of RNP complexes in human cells. We identify 1,428 protein complexes that associate with RNA, indicating that over 20% of known human protein complexes contain RNA. To explore the role of RNA in the assembly of each complex, we identify complexes that dissociate, change composition, or form stable protein-only complexes in the absence of RNA. Importantly, these data also provide specific novel insights into the function of well-studied protein complexes not previously known to associate with RNA, including replication factor C (RFC) and cytokinetic centralspindlin complex. Finally, we use our method to systematically identify cell-type specific RNA-associated proteins in mouse embryonic stem cells. We distribute these data as a resource, rna.MAP (rna.proteincomplexes.org) which provides a comprehensive dataset for the study of RNA-associated protein complexes. Our system thus provides a novel methodology for further explorations across human tissues and disease states, as well as throughout all domains of life.SummaryAn exploration of human protein complexes in the presence and absence of RNA reveals endogenous ribonucleoprotein complexes

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RNA Is a Double-Edged Sword in ALS Pathogenesis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.708181 ◽

2021 ◽

Vol 15 ◽

Author(s):

Benjamin L. Zaepfel ◽

Jeffrey D. Rothstein

Keyword(s):

Motor Neurons ◽

Cortical Neurons ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Small Subset ◽

Toxic Rna ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

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The Expanding Role of RNA-Binding Proteins in Neurodegeneration

Insights into Human Neurodegeneration: Lessons Learnt from Drosophila ◽

10.1007/978-981-13-2218-1_13 ◽

2019 ◽

pp. 373-403

Author(s):

Bhawana Maurya ◽

Satya Surabhi ◽

Pranjali Pandey ◽

Ashim Mukherjee ◽

Mousumi Mutsuddi

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins

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Sorting Mechanisms for MicroRNAs into Extracellular Vesicles and Their Associated Diseases

Cells ◽

10.3390/cells9041044 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1044 ◽

Cited By ~ 19

Author(s):

Michael Groot ◽

Heedoo Lee

Keyword(s):

Extracellular Vesicles ◽

Potential Role ◽

Rna Binding ◽

Rna Binding Proteins ◽

Transport Proteins ◽

Caveolin 1 ◽

Argonaute 2 ◽

Disease States ◽

Mirna Content

Extracellular vesicles (EV) are secretory membranous elements used by cells to transport proteins, lipids, mRNAs, and microRNAs (miRNAs). While their existence has been known for many years, only recently has research begun to identify their function in intercellular communication and gene regulation. Importantly, cells have the ability to selectively sort miRNA into EVs for secretion to nearby or distant targets. These mechanisms broadly include RNA-binding proteins such as hnRNPA2B1 and Argonaute-2, but also membranous proteins involved in EV biogenesis such as Caveolin-1 and Neural Sphingomyelinase 2. Moreover, certain disease states have also identified dysregulated EV-miRNA content, shedding light on the potential role of selective sorting in pathogenesis. These pathologies include chronic lung disease, immune response, neuroinflammation, diabetes mellitus, cancer, and heart disease. In this review, we will overview the mechanisms whereby cells selectively sort miRNA into EVs and also outline disease states where EV-miRNAs become dysregulated.

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