Binding Proteins
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2021 ◽  
Author(s):  
Ashish Kumar ◽  
Yuanzhi Lyu ◽  
Yuichi Yanagihashi ◽  
Chanikarn Chantarasrivong ◽  
Vladimir Majerciak ◽  
...  

Abstract In previous studies, we have shown that expression of a viral lncRNA, polyadenylated nuclear RNA (PAN RNA) is essential for inducible viral genomic looping and distal gene activation during Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation. Here we identify viral lncRNA binding proteins, and show that an underlying molecular mechanism regulating the KSHV latency-lytic replication switch is via a viral lncRNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. Proximity biotin labeling, single cell transcriptomics, and siRNA screening along with complementation studies identified that CHD4's enzymatic activity silences viral gene expression by preventing transcription factory formation. Furthermore, Capture Hi-C, Cleavage Under Targets and Release Using Nuclease (CUT&RUN), and proteomics approaches together identify KSHV episome docking sites on host chromosomes and colocalization with a CHD4 protein complex, ChAHP, at epigenetically active genomic regions. PAN RNA binds and competes with CHD4 DNA binding in vitro, and KSHV episomes detached from these host genomic loci sites when reactivation is triggered. Our studies suggest that CHD4 exhibits strong repressor function by preventing inducible genomic looping, and is therefore important for the ability of KSHV to establish and maintain latency in a "poised" state at selected host genomic loci.


Author(s):  
De-Li Shi ◽  
Raphaëlle Grifone

Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.


2021 ◽  
Vol 2 (4) ◽  
pp. 100819
Author(s):  
Michael Rosenberg ◽  
Vered Levy ◽  
Verena K. Maier ◽  
Barry Kesner ◽  
Roy Blum ◽  
...  

2021 ◽  
Author(s):  
Shunsuke Kawasaki ◽  
Hiroki Ono ◽  
Moe Hirosawa ◽  
Takeru Kuwabara ◽  
Hirohide Saito

The complexity of synthetic genetic circuits relies on repertories of biological circuitry with high orthogonality. Although post-transcriptional circuitry relying on RNA-binding proteins (RBPs) qualifies as a repertory, the limited pool of regulatory devices hinders network modularity and scalability. Here we propose CaRTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Genomic Engineering) to repurpose CRISPR-associated (Cas) proteins as translational modulators. We demonstrate that a set of Cas proteins are able to repress (OFF) or activate (ON) the translation of mRNAs that contain a Cas-binding RNA motif in the 5'-UTR. We designed 81 different types of translation OFF and ON switches and verified their functional characteristics. Many of them functioned as efficient translational regulators and showed orthogonality in mammalian cells. By interconnecting these switches, we designed and built artificial circuits, including 60 translational AND gates. Moreover, we show that various CRISPR-related technologies, including anti-CRISPR and split-Cas9 platforms, can be repurposed to control translation. Our Cas-mediated translational regulation is compatible with transcriptional regulation by Cas proteins and increases the complexity of synthetic circuits with fewer elements. CaRTRIDGE builds protein-responsive mRNA switches more than ever and leads to the development of both Cas-mediated genome editing and translational regulation technologies.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mandana Ameli-Mojarad ◽  
Melika Ameli-Mojarad ◽  
Mahrooyeh Hadizadeh ◽  
Chris Young ◽  
Hosna Babini ◽  
...  

AbstractColorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late detection plays role in one-third of annual mortality due to CRC. Therefore, it is essential to find a precise and optimal diagnostic and prognostic biomarker for the identification and treatment of colorectal tumorigenesis. Covalently closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have the same function as microRNA (miRNA) sponges, as regulators of splicing and transcription, and as interactors with RNA-binding proteins (RBPs). Therefore, circRNAs have been investigated as specific targets for diagnostic and prognostic detection of CRC. These non-coding RNAs are also linked to metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis, and drug resistance, illustrating the importance of understanding their involvement in the molecular mechanisms of development and progression of CRC. In this review, we present a detailed summary of recent findings relating to the dysregulation of circRNAs and their potential role in CRC.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Szu-Ning Lin ◽  
Remus T. Dame ◽  
Gijs J. L. Wuite

AbstractArchitectural DNA–binding proteins are involved in many important DNA transactions by virtue of their ability to change DNA conformation. Histone-like protein from E. coli strain U93, HU, is one of the most studied bacterial architectural DNA–binding proteins. Nevertheless, there is still a limited understanding of how the interactions between HU and DNA are affected by ionic conditions and the structure of DNA. Here, using optical tweezers in combination with fluorescent confocal imaging, we investigated how ionic conditions affect the interaction between HU and DNA. We directly visualized the binding and the diffusion of fluorescently labelled HU dimers on DNA. HU binds with high affinity and exhibits low mobility on the DNA in the absence of Mg2+; it moves 30-times faster and stays shorter on the DNA with 8 mM Mg2+ in solution. Additionally, we investigated the effect of DNA tension on HU–DNA complexes. On the one hand, our studies show that binding of HU enhances DNA helix stability. On the other hand, we note that the binding affinity of HU for DNA in the presence of Mg2+ increases at tensions above 50 pN, which we attribute to force-induced structural changes in the DNA. The observation that HU diffuses faster along DNA in presence of Mg2+ compared to without Mg2+ suggests that the free energy barrier for rotational diffusion along DNA is reduced, which can be interpreted in terms of reduced electrostatic interaction between HU and DNA, possibly coinciding with reduced DNA bending.


2021 ◽  
Author(s):  
Stephen W White ◽  
Charles O Rock ◽  
Emad Tajkhorshid ◽  
Jessica M Gullett ◽  
Maxime G Cuypers ◽  
...  

Fatty acid (FA) transfer proteins extract FA from membranes and sequester their ligand to facilitate its movement through the cytosol. While detailed views of soluble protein-FA complexes are available, how FA exchange occurs at the membrane has remained unknown. Staphylococcus aureus FakB1 is a prototypical bacterial FA transfer protein that binds palmitate within a narrow, buried tunnel. Here, we determine the conformational change from this closed state to an open state that engages the phospholipid bilayer. Upon membrane binding, a dynamic loop in FakB1 that covers the FA binding site disengages and folds into an amphipathic helix. This helix inserts below the phosphate plane of the bilayer to create a diffusion channel for the FA to exchange between the protein and the membrane. The structure of the bilayer-associated conformation of FakB1 has local similarities with mammalian FA binding proteins and provides a general conceptual framework for how these proteins interact with the membrane to promote lipid transfer.


2021 ◽  
Author(s):  
Yukun Jia ◽  
Zhan Peng ◽  
Guangye Wang

Abstract Background: RNA binding proteins (RBP) plays an important role in post-transcriptional regulation. Although the dysregulation of RBP expression is closely related to the occurrence and metastasis of a variety of tumors, there are few reports on RBP in endometrial carcinoma (UCEC). This study aims to establish a RBP-related prognostic model of UCEC. Methods: We downloaded UCEC gene expression and clinical information data from the Cancer Genome Atlas (TCGA) and GEO database, and determined RBPs that are differentially expressed between tumors and normal tissues. Then, used functional enrichment analysis to analyze the biological functions of the differentially expressed RBP. Used univariate Cox regression analysis to screen prognostic-related RBP and construct a prognostic model. Subsequently, Kaplan-Meier and recipient operating characteristic (ROC) curves were drawn to evaluate the model. Finally, established a nomogram. Results: This study identified 531 differentially expressed RBPs, including 325 up-regulated and 206 down-regulated RBPs, respectively. Then six independent prognostic-related RBPs (REXO2, MARS2, XPO5, YBX1, YBX2, and CELF4) were used to construct a prognostic model. According to this model, the overall survival (OS) of patients in the high-risk score group was significantly lower than that of the low-risk score group. In the training queue and the test queue, the areas under the ROC curve were 0.799 and 0.669, respectively, showing the moderate predictive value of the model. Conclusion: We have developed and validated the RBP-related prognostic model.


2021 ◽  
Vol 131 (18) ◽  
Author(s):  
Peter S. Choi ◽  
Andrei Thomas-Tikhonenko

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