scholarly journals miRNA-independent function of long noncoding pri-miRNA loci

2021 ◽  
Vol 118 (13) ◽  
pp. e2017562118
Author(s):  
Daniel He ◽  
David Wu ◽  
Soren Muller ◽  
Lin Wang ◽  
Parna Saha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Biology ◽  
Cell Types ◽  
Dna Looping ◽  
Gene Promoters ◽  
Functional Studies ◽  
A Genome ◽  
Genome Wide Data ◽  
Cell Propagation

Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1–independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.

scholarly journals The organisation and functions of local Ca2+ signals

2001 ◽  
Vol 114 (12) ◽  
pp. 2213-2222 ◽  
Author(s):  
Martin D. Bootman ◽  
Peter Lipp ◽  
Michael J. Berridge
Keyword(s):  
Cell Proliferation ◽  
Gene Transcription ◽  
Cell Biology ◽  
Building Blocks ◽  
Cell Types ◽  
Diverse Range ◽  
Cellular Processes ◽  
Different Cell Types ◽  
Intracellular Messenger ◽  
Sensory Mechanisms

Calcium (Ca2+) is a ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation. The ability of a simple ion such as Ca2+ to play a pivotal role in cell biology results from the facility that cells have to shape Ca2+ signals in space, time and amplitude. To generate and interpret the variety of observed Ca2+ signals, different cell types employ components selected from a Ca2+ signalling ‘toolkit’, which comprises an array of homeostatic and sensory mechanisms. By mixing and matching components from the toolkit, cells can obtain Ca2+ signals that suit their physiology. Recent studies have demonstrated the importance of local Ca2+ signals in defining the specificity of the interaction of Ca2+ with its targets. Furthermore, local Ca2+ signals are the triggers and building blocks for larger global signals that propagate throughout cells.

scholarly journals Schlafens: Emerging Proteins in Cancer Cell Biology

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2238
Author(s):  
Sarmad Al-Marsoummi ◽  
Emilie E. Vomhof-DeKrey ◽  
Marc D. Basson
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Biology ◽  
Cancer Biology ◽  
Immune Cell ◽  
Biological Functions ◽  
Cancer Types ◽  
Opposing Effects ◽  
High Degree ◽  
Human And Mouse

Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.

scholarly journals RNA-guided cell targeting with CRISPR/RfxCas13d collateral activity in human cells

2021 ◽  
Author(s):  
Peiguo Shi ◽  
Michael R Murphy ◽  
Alexis O Aparicio ◽  
Jordan S Kesner ◽  
Zhou Fang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Single Cell ◽  
State Transition ◽  
Cell Types ◽  
Rapid Identification ◽  
Human Cells ◽  
Single Cell Sequencing ◽  
Functional Studies ◽  
Single Marker ◽  
Inhibit Cell Proliferation

While single-cell sequencing has allowed rapid identification of novel cell types or states and associated RNA markers, functional studies remain challenging due to the lack of tools that are able to target specific cells based on these markers. Here we show that targeting a single marker RNA with CRISPR/RfxCas13d led to collateral transcriptome destruction in human cells, which can be harnessed to inhibit cell proliferation or to suppress cell state transition.

scholarly journals Mammalian cell proliferation requires noncatalytic functions of O-GlcNAc transferase

2021 ◽  
Vol 118 (4) ◽  
pp. e2016778118
Author(s):  
Zebulon G. Levine ◽  
Sarah C. Potter ◽  
Cassandra M. Joiner ◽  
George Q. Fei ◽  
Behnam Nabet ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Mammalian Cell ◽  
Control Cell ◽  
Cell Types ◽  
Cell Physiology ◽  
Enzymatic Reactions ◽  
A Cell ◽  
Glcnac Transferase ◽  
Catalytic Functions

O-GlcNAc transferase (OGT), found in the nucleus and cytoplasm of all mammalian cell types, is essential for cell proliferation. Why OGT is required for cell growth is not known. OGT performs two enzymatic reactions in the same active site. In one, it glycosylates thousands of different proteins, and in the other, it proteolytically cleaves another essential protein involved in gene expression. Deconvoluting OGT’s myriad cellular roles has been challenging because genetic deletion is lethal; complementation methods have not been established. Here, we developed approaches to replace endogenous OGT with separation-of-function variants to investigate the importance of OGT’s enzymatic activities for cell viability. Using genetic complementation, we found that OGT’s glycosyltransferase function is required for cell growth but its protease function is dispensable. We next used complementation to construct a cell line with degron-tagged wild-type OGT. When OGT was degraded to very low levels, cells stopped proliferating but remained viable. Adding back catalytically inactive OGT rescued growth. Therefore, OGT has an essential noncatalytic role that is necessary for cell proliferation. By developing a method to quantify how OGT’s catalytic and noncatalytic activities affect protein abundance, we found that OGT’s noncatalytic functions often affect different proteins from its catalytic functions. Proteins involved in oxidative phosphorylation and the actin cytoskeleton were especially impacted by the noncatalytic functions. We conclude that OGT integrates both catalytic and noncatalytic functions to control cell physiology.

scholarly journals An atlas of silencer elements for the human and mouse genomes

2018 ◽  
Author(s):  
Naresh Doni Jayavelu ◽  
Ajay Jajodia ◽  
Arpit Mishra ◽  
R. David Hawkins
Keyword(s):  
Cell Types ◽  
Regulatory Elements ◽  
Mouse Cell ◽  
Support Vector ◽  
General Strategy ◽  
Gene Promoters ◽  
Genome Wide ◽  
A Genome ◽  
Silencer Elements ◽  
Human And Mouse

ABSTRACTThe study of gene regulation is dominated by a focus on the control of gene activation or controlling an increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have allowed for the global mapping of enhancer cis-regulatory elements, however, the identification of silencer elements by computational or experimental approaches in a genome-wide manner are lacking. We present a simple but powerful computational approach to identify putative silencers genome-wide. We used a series of consortia data to predict silencers in over 100 human and mouse cell or tissue types. We performed several analyses to determine if these elements exhibited characteristics expected of a silencers. Motif enrichment analyses on putative silencers determined that motifs belonging to known transcriptional repressors are enriched, as well as overlapping known transcription repressor binding sites. Leveraging promoter capture HiC data from several human and mouse cell types, we found that over 50% of putative silencer elements are interacting with gene promoters having very low to no expression. Next, to validate our silencer predictions, we quantified silencer activity using massively parallel reporter assays (MPRAs) on 7500 selected elements in K562 cells. We trained a support vector machine model classifier on MPRA data and used it to refine potential silencers in other cell types. We also show that similar to enhancer elements, silencer elements are enriched in disease-associated variants. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.

scholarly journals Extracellular vesicles: communication, coercion, and conditioning

2013 ◽  
Vol 24 (9) ◽  
pp. 1253-1259 ◽  
Author(s):  
David A. Shifrin ◽  
Michelle Demory Beckler ◽  
Robert J. Coffey ◽  
Matthew J. Tyska
Keyword(s):  
Extracellular Vesicles ◽  
Extracellular Space ◽  
Cell Biology ◽  
Biological Significance ◽  
Local Environment ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Functional Studies ◽  
Wide Range ◽  
Physiological Homeostasis

Cells communicate with neighboring cells and condition their local environment by secreting soluble factors into the extracellular space. These well-studied facets of cell biology are essential for the establishment and maintenance of physiological homeostasis. However, accumulating evidence has revealed that specific ligands, enzymes, and macromolecules are distributed into the extracellular space by virtue of their association with small vesicles, which are released by a variety of cell types. Although the biological significance of such vesicles was initially debated, purification and subsequent functional studies have shown that these extracellular vesicles are bioactive organelles carrying a wide range of protein and nucleic acid cargoes. In many cases these vesicles are laden with molecules that are involved in cell signaling, although other diverse functions are being revealed at a rapid pace. In this Perspective, we discuss recent developments in the understanding of the major pathways of extracellular vesicle biogenesis and how these vesicles contribute to the maintenance of physiological homeostasis.

scholarly journals Monocarboxylate Transporter 8 in Neuronal Cell Growth

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1961-1969 ◽  
Author(s):  
S. R. James ◽  
J. A. Franklyn ◽  
B. J. Reaves ◽  
V. E. Smith ◽  
S. Y. Chan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone ◽  
Cell Growth ◽  
Neural Development ◽  
Neuronal Cell ◽  
Normal Growth ◽  
Cell Types ◽  
Monocarboxylate Transporter ◽  
Dependent Manner ◽  
Nt2 Cells

Thyroid hormones are essential for the normal growth and development of the fetus, and even small alterations in maternal thyroid hormone status during early pregnancy may be associated with neurodevelopmental abnormalities in childhood. Mutations in the novel and specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) have been associated with severe neurodevelopmental impairment. However, the mechanism by which MCT8 influences neural development remains poorly defined. We have therefore investigated the effect of wild-type (WT) MCT8, and the previously reported L471P mutant, on the growth and function of human neuronal precursor NT2 cells as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localized to the plasma membrane in NT2 cells and increased T3 uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum and displayed no T3 transport activity. Transient overexpression of WT and mutant MCT8 proteins failed to induce endoplasmic reticular stress or apoptosis. However, MCT8 overexpression significantly repressed cell proliferation in each cell type in both the presence and absence of the active thyroid hormone T3 and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, small interfering RNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T3 uptake. Given that T3 stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T3 transport, mediated through the modulation of cell proliferation in the developing brain.

scholarly journals Bacterial cell proliferation: from molecules to cells

2020 ◽  
Author(s):  
Alix Meunier ◽  
François Cornet ◽  
Manuel Campos
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Growth ◽  
Bacterial Cell ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Cell Physiology ◽  
Precise Knowledge

ABSTRACT Bacterial cell proliferation is highly efficient, both because bacteria grow fast and multiply with a low failure rate. This efficiency is underpinned by the robustness of the cell cycle and its synchronization with cell growth and cytokinesis. Recent advances in bacterial cell biology brought about by single-cell physiology in microfluidic chambers suggest a series of simple phenomenological models at the cellular scale, coupling cell size and growth with the cell cycle. We contrast the apparent simplicity of these mechanisms based on the addition of a constant size between cell cycle events (e.g. two consecutive initiation of DNA replication or cell division) with the complexity of the underlying regulatory networks. Beyond the paradigm of cell cycle checkpoints, the coordination between the DNA and division cycles and cell growth is largely mediated by a wealth of other mechanisms. We propose our perspective on these mechanisms, through the prism of the known crosstalk between DNA replication and segregation, cell division and cell growth or size. We argue that the precise knowledge of these molecular mechanisms is critical to integrate the diverse layers of controls at different time and space scales into synthetic and verifiable models.

scholarly journals Conserved epigenetic regulatory logic infers genes governing cell identity

2019 ◽  
Author(s):  
Woo Jun Shim ◽  
Enakshi Sinniah ◽  
Jun Xu ◽  
Burcu Vitrinel ◽  
Michael Alexanian ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Biology ◽  
Peer Review Process ◽  
Cell Types ◽  
Computational Method ◽  
Cell Identity ◽  
Genome Wide ◽  
Fundamental Goal ◽  
A Genome ◽  
Wide Range

SUMMARYDetermining genes orchestrating cell differentiation in development and disease remains a fundamental goal of cell biology. This study establishes a genome-wide metric based on the gene-repressive tri-methylation of histone 3 lysine 27 (H3K27me3) across hundreds of diverse cell types to identify genetic regulators of cell differentiation. We introduce a computational method, TRIAGE, that uses discordance between gene-repressive tendency and expression to identify genetic drivers of cell identity. We apply TRIAGE to millions of genome-wide single-cell transcriptomes, diverse omics platforms, and eukaryotic cells and tissue types. Using a wide range of data, we validate TRIAGE’s performance for identifying cell-type specific regulatory factors across diverse species including human, mouse, boar, bird, fish, and tunicate. Using CRISPR gene editing, we use TRIAGE to experimentally validate RNF220 as a regulator of Ciona cardiopharyngeal development and SIX3 as required for differentiation of endoderm in human pluripotent stem cells. A record of this paper’s Transparent Peer Review process is included in the Supplemental Information.

ARFGAP3 an androgen target gene promotes prostate cancer cell proliferation and migration.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Biology ◽  
Adaptor Protein ◽  
Cancer Cell Proliferation ◽  
Lncap Cells ◽  
Gtpase Activating Protein ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgiapparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 toprostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) atboth the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells withFLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation andmigration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein thatis important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed thatARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostatespecificantigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown byluciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promoteprostate cancer cell proliferation and migration in collaboration with paxillin.

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