scholarly journals Regulation of gene transcription by Polycomb proteins

2015 ◽  
Vol 1 (11) ◽  
pp. e1500737 ◽  
Author(s):  
Sergi Aranda ◽  
Gloria Mas ◽  
Luciano Di Croce
Keyword(s):  
Gene Transcription ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Mechanisms Of Action ◽  
Polycomb Group ◽  
Chromatin Conformation ◽  
Polycomb Proteins ◽  
Positional Identity ◽  
And Function

The Polycomb group (PcG) of proteins defines a subset of factors that physically associate and function to maintain the positional identity of cells from the embryo to adult stages. PcG has long been considered a paradigmatic model for epigenetic maintenance of gene transcription programs. Despite intensive research efforts to unveil the molecular mechanisms of action of PcG proteins, several fundamental questions remain unresolved: How many different PcG complexes exist in mammalian cells? How are PcG complexes targeted to specific loci? How does PcG regulate transcription? In this review, we discuss the diversity of PcG complexes in mammalian cells, examine newly identified modes of recruitment to chromatin, and highlight the latest insights into the molecular mechanisms underlying the function of PcGs in transcription regulation and three-dimensional chromatin conformation.

scholarly journals Gene Transcription as a Therapeutic Target in Leukemia

2021 ◽  
Vol 22 (14) ◽  
pp. 7340
Author(s):  
Alvina I. Khamidullina ◽  
Ekaterina A. Varlamova ◽  
Nour Alhuda Hammoud ◽  
Margarita A. Yastrebova ◽  
Alexandra V. Bruter
Keyword(s):  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Mechanisms Of Action ◽  
Special Program ◽  
Cell Plasticity ◽  
Hematopoietic Stem ◽  
Promising Strategy ◽  
Tumor Cell Plasticity ◽  
Transcriptional Landscape

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials.

scholarly journals Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 358 ◽  
Author(s):  
Diana C. Muñoz-Lasso ◽  
Carlos Romá-Mateo ◽  
Federico V. Pallardó ◽  
Pilar Gonzalez-Cabo
Keyword(s):  
Neurological Disorders ◽  
Actin Filaments ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Three Dimensional ◽  
Cytoskeletal Proteins ◽  
Dimensional Lattice ◽  
New Treatments ◽  
And Function

Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders.

scholarly journals The Drosophila snr1 and brm proteins are related to yeast SWI/SNF proteins and are components of a large protein complex.

1995 ◽  
Vol 6 (7) ◽  
pp. 777-791 ◽  
Author(s):  
A K Dingwall ◽  
S J Beek ◽  
C M McCallum ◽  
J W Tamkun ◽  
G V Kalpana ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Protein Complex ◽  
Molecular Mechanisms ◽  
Protein A ◽  
Polycomb Group ◽  
Homeotic Gene ◽  
Spatial And Temporal Patterns ◽  
Trithorax Group ◽  
Activator Proteins ◽  
A Subunit

During most of Drosophila development the regulation of homeotic gene transcription is controlled by two groups of regulatory genes, the trithorax group of activators and the Polycomb group of repressors. brahma (brm), a member of the trithorax group, encodes a protein related to the yeast SWI2/SNF2 protein, a subunit of a protein complex that assists sequence-specific activator proteins by alleviating the repressive effects of chromatin. To learn more about the molecular mechanisms underlying the regulation of homeotic gene transcription, we have investigated whether a similar complex exists in flies. We identified the Drosophila snr1 gene, a potential homologue of the yeast SNF5 gene that encodes a subunit of the yeast SWI/SNF complex. The snr1 gene is essential and genetically interacts with brm and trithorax (trx), suggesting cooperation in regulating homeotic gene transcription. The spatial and temporal patterns of expression of snr1 are similar to those of brm. The snr1 and brm proteins are present in a large (> 2 x 10(6) Da) complex, and they co-immunoprecipitate from Drosophila extracts. These findings provide direct evidence for conservation of the SWI/SNF complex in higher eucaryotes and suggest that the Drosophila brm/snr1 complex plays an important role in maintaining homeotic gene transcription during development by counteracting the repressive effects of chromatin.

scholarly journals Structure and function of outer dynein arm intermediate and light chain complex

2016 ◽  
Vol 27 (7) ◽  
pp. 1051-1059 ◽  
Author(s):  
Toshiyuki Oda ◽  
Tatsuki Abe ◽  
Haruaki Yanagisawa ◽  
Masahide Kikkawa
Keyword(s):  
Molecular Mechanisms ◽  
Electron Tomography ◽  
3D Structure ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Chain Complex ◽  
Flagellar Motility ◽  
Chemically Induced Dimerization ◽  
And Function

The outer dynein arm (ODA) is a molecular complex that drives the beating motion of cilia/flagella. Chlamydomonas ODA is composed of three heavy chains (HCs), two ICs, and 11 light chains (LCs). Although the three-dimensional (3D) structure of the whole ODA complex has been investigated, the 3D configurations of the ICs and LCs are largely unknown. Here we identified the 3D positions of the two ICs and three LCs using cryo–electron tomography and structural labeling. We found that these ICs and LCs were all localized at the root of the outer-inner dynein (OID) linker, designated the ODA-Beak complex. Of interest, the coiled-coil domain of IC2 extended from the ODA-Beak to the outer surface of ODA. Furthermore, we investigated the molecular mechanisms of how the OID linker transmits signals to the ODA-Beak, by manipulating the interaction within the OID linker using a chemically induced dimerization system. We showed that the cross-linking of the OID linker strongly suppresses flagellar motility in vivo. These results suggest that the ICs and LCs of the ODA form the ODA-Beak, which may be involved in mechanosignaling from the OID linker to the HCs.

scholarly journals Light Sheet Illumination for 3D Single-Molecule Super-Resolution Imaging of Neuronal Synapses

2021 ◽  
Vol 13 ◽  
Author(s):  
Gabriella Gagliano ◽  
Tyler Nelson ◽  
Nahima Saliba ◽  
Sofía Vargas-Hernández ◽  
Anna-Karin Gustavsson
Keyword(s):  
Single Molecule ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Super Resolution ◽  
Light Sheet ◽  
Three Dimensions ◽  
Single Molecule Imaging ◽  
Single Molecule Tracking ◽  
Resolution Imaging

The function of the neuronal synapse depends on the dynamics and interactions of individual molecules at the nanoscale. With the development of single-molecule super-resolution microscopy over the last decades, researchers now have a powerful and versatile imaging tool for mapping the molecular mechanisms behind the biological function. However, imaging of thicker samples, such as mammalian cells and tissue, in all three dimensions is still challenging due to increased fluorescence background and imaging volumes. The combination of single-molecule imaging with light sheet illumination is an emerging approach that allows for imaging of biological samples with reduced fluorescence background, photobleaching, and photodamage. In this review, we first present a brief overview of light sheet illumination and previous super-resolution techniques used for imaging of neurons and synapses. We then provide an in-depth technical review of the fundamental concepts and the current state of the art in the fields of three-dimensional single-molecule tracking and super-resolution imaging with light sheet illumination. We review how light sheet illumination can improve single-molecule tracking and super-resolution imaging in individual neurons and synapses, and we discuss emerging perspectives and new innovations that have the potential to enable and improve single-molecule imaging in brain tissue.

scholarly journals The order of macrophage 4D genome coordinates gene transcription during differentiation and infection

2021 ◽  
Author(s):  
Gang Cao ◽  
Da Lin ◽  
Weize Xu ◽  
Ping Hong ◽  
Chengchao Wu ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Genome Organization ◽  
Target Genes ◽  
Three Dimensional ◽  
Drug Candidate ◽  
Genome Architecture ◽  
Chromatin Conformation ◽  
Chromatin Loop ◽  
Target Genome ◽  
Organizational Patterns

Abstract The highly organized three-dimensional genome is crucial for gene transcription. However, it remains elusive how the order of the genome architecture related to its function. Here, we developed a single-cell Hi-C method and proposed TAD “degree of disorder” as a measure of genome organizational patterns, which is correlated with the chromatin epigenetic states, gene expression and co-regulation, and chromatin structure variability in individual cells. Upon Mycobacterium tuberculosis infection, NF-κB enters into the nucleus, binds to the target genome regions and initiates systematic chromatin conformation reorganization. Furthermore, we identified a remote NF-κB enriched enhancer promotes the expression of PD-L1 through chromatin loop, which could be a potential anti-tuberculosis and even anti-tumor therapeutic target. The integrated Hi-C, eQTL, and GWAS analysis depicted the atlas of the long-range target genes of tuberculosis susceptible loci. Among which SNP rs1873613 is located in the anchor of a dynamic chromatin loop with LRRK2, whose inhibitor AdoCbl could be an anti-tuberculosis drug candidate. Our study provides comprehensive resources for the 4D genome of immunocytes and sheds insights into the genome organization order and the coordinated gene transcription.

scholarly journals The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mayra Furlan-Magaril ◽  
Masami Ando-Kuri ◽  
Rodrigo G. Arzate-Mejía ◽  
Jörg Morf ◽  
Jonathan Cairns ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Regulatory Elements ◽  
Chromatin Conformation ◽  
Gene Promoters ◽  
Circadian Gene ◽  
Circadian Genes ◽  
Over Time

Abstract Background Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized. Results Here we measure changes in the spatial chromatin conformation in mouse liver using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription. We find topologically associating domains harboring circadian genes that switch assignments between the transcriptionally active and inactive compartment at different hours of the day, while their boundaries stably maintain their structure over time. To study chromatin contacts of promoters at high resolution over time, we apply promoter capture Hi-C. We find circadian gene promoters displayed a maximal number of chromatin contacts at the time of their peak transcriptional output. Furthermore, circadian genes, as well as contacted and transcribed regulatory elements, reach maximal expression at the same timepoints. Anchor sites of circadian gene promoter loops are enriched in DNA binding sites for liver nuclear receptors and other transcription factors, some exclusively present in either rhythmic or stable contacts. Finally, by comparing the interaction profiles between core clock and output circadian genes, we show that core clock interactomes are more dynamic compared to output circadian genes. Conclusion Our results identify chromatin conformation dynamics at different scales that parallel oscillatory gene expression and characterize the repertoire of regulatory elements that control circadian gene transcription through rhythmic or stable chromatin configurations.

Functional architecture in the cell nucleus

2001 ◽  
Vol 356 (2) ◽  
pp. 297-310 ◽  
Author(s):  
Miroslav DUNDR ◽  
Tom MISTELI
Keyword(s):  
Gene Expression ◽  
Cell Nucleus ◽  
Molecular Mechanisms ◽  
Dynamic Properties ◽  
Three Dimensional ◽  
Nuclear Architecture ◽  
Structural Framework ◽  
And Function ◽  
Biological Methods

The major functions of the cell nucleus, including transcription, pre-mRNA splicing and ribosome assembly, have been studied extensively by biochemical, genetic and molecular methods. An overwhelming amount of information about their molecular mechanisms is available. In stark contrast, very little is known about how these processes are integrated into the structural framework of the cell nucleus and how they are spatially and temporally co-ordinated within the three-dimensional confines of the nucleus. It is also largely unknown how nuclear architecture affects gene expression. In order to understand how genomes are organized, and how they function, the basic principles that govern nuclear architecture and function must be uncovered. Recent work combining molecular, biochemical and cell biological methods is beginning to shed light on how the nucleus functions and how genes are expressed in vivo. It has become clear that the nucleus contains distinct compartments and that many nuclear components are highly dynamic. Here we describe the major structural compartments of the cell nucleus and discuss their established and proposed functions. We summarize recent observations regarding the dynamic properties of chromatin, mRNA and nuclear proteins, and we consider the implications these findings have for the organization of nuclear processes and gene expression. Finally, we speculate that self-organization might play a substantial role in establishing and maintaining nuclear organization.

scholarly journals 3-Dimensional architecture of the human multi-tRNA synthetase complex

2020 ◽  
Vol 48 (15) ◽  
pp. 8740-8754 ◽  
Author(s):  
Krishnendu Khan ◽  
Camelia Baleanu-Gogonea ◽  
Belinda Willard ◽  
Valentin Gogonea ◽  
Paul L Fox
Keyword(s):  
Mammalian Cells ◽  
Structural Model ◽  
Structural Information ◽  
Three Dimensional ◽  
Trna Synthetase ◽  
3 Dimensional ◽  
Trna Synthetases ◽  
Binding Domains ◽  
Cross Links ◽  
And Function

Abstract In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). AARSs have critical roles in interpretation of the genetic code during protein synthesis, and in non-canonical functions unrelated to translation. Nonetheless, the structure and function of the MSC remain unclear. Partial or complete crystal structures of all MSC constituents have been reported; however, the structure of the holo-MSC has not been resolved. We have taken advantage of cross-linking mass spectrometry (XL-MS) and molecular docking to interrogate the three-dimensional architecture of the MSC in human HEK293T cells. The XL-MS approach uniquely provides structural information on flexibly appended domains, characteristic of nearly all MSC constituents. Using the MS-cleavable cross-linker, disuccinimidyl sulfoxide, inter-protein cross-links spanning all MSC constituents were observed, including cross-links between eight protein pairs not previously known to interact. Intra-protein cross-links defined new structural relationships between domains in several constituents. Unexpectedly, an asymmetric AARS distribution was observed featuring a clustering of tRNA anti-codon binding domains on one MSC face. Possibly, the non-uniform localization improves efficiency of delivery of charged tRNA’s to an interacting ribosome during translation. In summary, we show a highly compact, 3D structural model of the human holo-MSC.

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