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Author

Weirui Ma

Bio: Weirui Ma is an academic researcher from Memorial Sloan Kettering Cancer Center. The author has contributed to research in topics: Enhancer & Three prime untranslated region. The author has an hindex of 4, co-authored 6 publications receiving 156 citations.

Papers
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Journal ArticleDOI
29 Nov 2018-Cell
TL;DR: It is discovered that the broadly expressed RNA-binding protein TIS11B forms a membraneless organelle, called TIS granule, that enriches membrane protein-encoding mRNAs with multiple AU-rich elements, thus allowing increased surface expression and functional diversity of proteins, including CD47 and PD-L1.

216 citations

Journal ArticleDOI
02 Mar 2021-eLife
TL;DR: In this paper, the TIS granule network is shown to be a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions.
Abstract: Liquid-like condensates have been thought to be sphere-like. Recently, various condensates with filamentous morphology have been observed in cells. One such condensate is the TIS granule network that shares a large surface area with the rough endoplasmic reticulum and is important for membrane protein trafficking. It has been unclear how condensates with mesh-like shapes but dynamic protein components are formed. In vitro and in vivo reconstitution experiments revealed that the minimal components are a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions. mRNAs with large unstructured regions have a high propensity to form a pervasive intermolecular interaction network that acts as condensate skeleton. The underlying RNA matrix prevents full fusion of spherical liquid-like condensates, thus driving the formation of irregularly shaped membraneless organelles. The resulting large surface area may promote interactions at the condensate surface and at the interface with other organelles.

61 citations

Posted ContentDOI
14 Feb 2020-bioRxiv
TL;DR: The TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum, and the data suggests that TISgranules concentrate m RNAs that assist protein folding.
Abstract: Summary The TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum. Most known biomolecular condensates are sphere-like, but TIS granules have a mesh-like morphology. Through in vivo and in vitro reconstitution experiments we discovered that this shape is generated by extensive intermolecular RNA-RNA interactions. They are mostly accomplished by mRNAs with large unstructured regions in their 3′UTRs that we call intrinsically disordered regions (IDRs). As AU-rich RNA is a potent chaperone that suppresses protein aggregation and is overrepresented in mRNAs with IDRs, our data suggests that TIS granules concentrate mRNAs that assist protein folding. In addition, the proximity of translating mRNAs in TIS granule networks may enable co-translational protein complex formation.

17 citations

Posted ContentDOI
17 Aug 2020-bioRxiv
TL;DR: It is found that enhancers are widespread regulators of PAS cleavage and consistently increase cleavage of proximal and weak PAS, thus changing 3’UTR isoform usage and protein activity, as PTEN proteins translated from the alternative 3”utR isoforms differ in intrinsic lipid phosphatase activity.
Abstract: Summary Enhancers are DNA elements that increase gene expression. mRNA production is determined by transcript production and polyadenylation site (PAS) cleavage activity. We established an assay to measure enhancer-dependent PAS cleavage activity in human cells because PAS cleavage may control alternative 3’UTR isoform expression. We found that enhancers are widespread regulators of PAS cleavage and consistently increase cleavage of proximal and weak PAS. Half of tested transcription factors exclusively regulated PAS cleavage without affecting transcript production, whereas co-activators changed both parameters. Deletion of an endogenous enhancer of PTEN did not change gene-level mRNA or protein abundance but affected expression of alternative mRNA transcripts, thus preventing 3’UTR shortening. Our data reveal that in addition to controlling transcript production, enhancers also regulate PAS cleavage, thus changing 3’UTR isoform usage and protein activity, as PTEN proteins translated from the alternative 3’UTR isoforms differ in intrinsic lipid phosphatase activity despite having identical amino acid sequences.

11 citations

Journal ArticleDOI
TL;DR: In this article , the authors investigated if transcriptional enhancers regulate mRNA expression and 3'UTR isoform expression and found that enhancers increase transcript production when paired with single-UTR gene promoters.
Abstract: Multi-UTR genes are widely transcribed and express their alternative 3'UTR isoforms in a cell type-specific manner. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate 3'UTR isoform expression. Endogenous enhancer deletion of the multi-UTR gene PTEN did not impair transcript production but prevented 3'UTR isoform switching which was recapitulated by silencing of an enhancer-bound transcription factor. In reporter assays, enhancers increase transcript production when paired with single-UTR gene promoters. However, when combined with multi-UTR gene promoters, they change 3'UTR isoform expression by increasing 3' end processing activity of polyadenylation sites. Processing activity of polyadenylation sites is affected by transcription factors, including NF-κB and MYC, transcription elongation factors, chromatin remodelers, and histone acetyltransferases. As endogenous cell type-specific enhancers are associated with genes that increase their short 3'UTRs in a cell type-specific manner, our data suggest that transcriptional enhancers integrate cellular signals to regulate cell type-and condition-specific 3'UTR isoform expression.

11 citations


Cited by
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Journal ArticleDOI
TL;DR: A framework for the study of condensate functions across these cellular length scales is provided, offering to bring new understanding of biological processes.
Abstract: Biomolecular condensates are found throughout eukaryotic cells, including in the nucleus, in the cytoplasm and on membranes. They are also implicated in a wide range of cellular functions, organizing molecules that act in processes ranging from RNA metabolism to signalling to gene regulation. Early work in the field focused on identifying condensates and understanding how their physical properties and regulation arise from molecular constituents. Recent years have brought a focus on understanding condensate functions. Studies have revealed functions that span different length scales: from molecular (modulating the rates of chemical reactions) to mesoscale (organizing large structures within cells) to cellular (facilitating localization of cellular materials and homeostatic responses). In this Roadmap, we discuss representative examples of biochemical and cellular functions of biomolecular condensates from the recent literature and organize these functions into a series of non-exclusive classes across the different length scales. We conclude with a discussion of areas of current interest and challenges in the field, and thoughts about how progress may be made to further our understanding of the widespread roles of condensates in cell biology.

355 citations

Journal ArticleDOI
TL;DR: In the past decade, it is has become clear that Membrane Contact Sites (MCSs) have a much broader range of critical roles in cells than was initially thought as mentioned in this paper, and functions for MCSs in intracellular signalling such as autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have been reported.
Abstract: Organelles compartmentalize eukaryotic cells, enhancing their ability to respond to environmental and developmental changes. One way in which organelles communicate and integrate their activities is by forming close contacts, often called 'membrane contact sites' (MCSs). Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of critical roles in cells than was initially thought. Indeed, functions for MCSs in intracellular signalling (particularly calcium signalling, reactive oxygen species signalling and lipid signalling), autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have now been reported.

320 citations

Journal ArticleDOI
TL;DR: The experimental and computational methods that have enabled the global mapping of mRNA and of long non-coding RNA 3ʹ ends, quantification of the resulting isoforms and the discovery of regulators of alternative cleavage and polyadenylation (APA) are reviewed.
Abstract: Most human genes have multiple sites at which RNA 3' end cleavage and polyadenylation can occur, enabling the expression of distinct transcript isoforms under different conditions. Novel methods to sequence RNA 3' ends have generated comprehensive catalogues of polyadenylation (poly(A)) sites; their analysis using innovative computational methods has revealed how poly(A) site choice is regulated by core RNA 3' end processing factors, such as cleavage factor I and cleavage and polyadenylation specificity factor, as well as by other RNA-binding proteins, particularly splicing factors. Here, we review the experimental and computational methods that have enabled the global mapping of mRNA and of long non-coding RNA 3' ends, quantification of the resulting isoforms and the discovery of regulators of alternative cleavage and polyadenylation (APA). We highlight the different types of APA-derived isoforms and their functional differences, and illustrate how APA contributes to human diseases, including cancer and haematological, immunological and neurological diseases.

250 citations

Journal ArticleDOI
TL;DR: Three key cellular mechanisms that enable the control of biomolecular phase separation are reviewed: membrane surfaces, post-translational modifications, and active processes; how these mechanisms may function in concert to provide robust control over biomolescular condensates is discussed.

198 citations

Journal ArticleDOI
TL;DR: Condensation of N-protein is RNA sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules, and presents a screenable process for identifying antiviral compounds effective against SARS-CoV-2.

197 citations