scholarly journals Local Enrichment of HP1alpha at Telomeres Alters Their Structure and Regulation of Telomere Protection

2018 ◽  
Author(s):  
Tracy T. Chow ◽  
Xiaoyu Shi ◽  
Jen-Hsuan Wei ◽  
Juan Guan ◽  
Guido Stadler ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Molecular Mechanisms ◽  
Super Resolution ◽  
Telomere Maintenance ◽  
Heterochromatin Protein ◽  
New Approach ◽  
Telomere Protection ◽  
Telomeric Structure ◽  
Local Enrichment ◽  
Chromo Shadow Domain

AbstractEnhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents a new approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

scholarly journals HP1 drives de novo 3D genome reorganization in early Drosophila embryos

Nature ◽  
2021 ◽  
Author(s):  
Fides Zenk ◽  
Yinxiu Zhan ◽  
Pavel Kos ◽  
Eva Löser ◽  
Nazerke Atinbayeva ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Early Embryo ◽  
Heterochromatin Protein ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Genome Reorganization

AbstractFundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown1,2. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

scholarly journals Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Tracy T. Chow ◽  
Xiaoyu Shi ◽  
Jen-Hsuan Wei ◽  
Juan Guan ◽  
Guido Stadler ◽  
...  
Keyword(s):  
Telomere Protection ◽  
Local Enrichment

Medicine

Mind-Society ◽  
2019 ◽  
pp. 259-291
Author(s):  
Paul Thagard
Keyword(s):  
Mental Illness ◽  
Molecular Mechanisms ◽  
Social Cognitive ◽  
Neural Mechanisms ◽  
Mental Illnesses ◽  
New Approach ◽  
Treatment Of Depression ◽  
Repair Mechanisms ◽  
Multiple Levels ◽  
Simple Reduction

All mental illnesses involve breakdowns in neural mechanisms for emotions that do not simply reduce to isolated mental, social, or chemical causes. The case of depression shows how illness results from the interaction of many causes that can be social, cognitive, neural, and molecular. Depression emerges from the interactions of mechanisms at all of these levels in a way that exemplifies emergence rather than simple reduction. Accordingly, treatment of depression often benefits from trying to repair mechanisms at multiple levels, most commonly by employing psychotherapy to make changes in mental representations and by employing antidepressants to change neurochemistry. Social cognitivism, the approach that integrates social, mental, neural, and molecular mechanisms, provides a new approach to explaining mental illness thanks to semantic pointer theories of cognition and communication.

scholarly journals Molecular mechanisms of telomere biology disorders

2020 ◽  
pp. jbc.REV120.014017
Author(s):  
Sherilyn Grill ◽  
Jayakrishnan Nandakumar
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Significant Proportion ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Genetic Mutations ◽  
Hematopoietic Stem ◽  
Telomere Biology ◽  
Underlying Mechanisms

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita (DC), pulmonary fibrosis (PF) and aplastic anemia (AA), is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin, and the telomerase RNA maturation component PARN, affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of DC mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pin-point disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

scholarly journals A New Approach to Super-Resolution Microscopy

2015 ◽  
Vol 23 (3) ◽  
pp. 8-11
Author(s):  
Stephen W. Carmichael
Keyword(s):  
Super Resolution ◽  
New Approach ◽  
Super Resolution Microscopy

scholarly journals Investigating Molecular Mechanisms of IgE-Mediated Signaling at Super Resolution

2016 ◽  
Vol 110 (3) ◽  
pp. 87a
Author(s):  
Eshan Mitra ◽  
Sarah A. Shelby ◽  
David Holowka ◽  
Barbara Baird
Keyword(s):  
Molecular Mechanisms ◽  
Super Resolution ◽  
Ige Mediated

scholarly journals Rab1 interacts with GOLPH3 and controls Golgi structure and contractile ring constriction during cytokinesis in Drosophila melanogaster

Open Biology ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. 160257 ◽  
Author(s):  
Stefano Sechi ◽  
Anna Frappaolo ◽  
Roberta Fraschini ◽  
Luisa Capalbo ◽  
Marco Gottardo ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Super Resolution ◽  
Cleavage Furrow ◽  
Contractile Ring ◽  
Cog Complex ◽  
Dividing Cells ◽  
Ring Constriction ◽  
Phosphatidylinositol 4

Cytokinesis requires a tight coordination between actomyosin ring constriction and new membrane addition along the ingressing cleavage furrow. However, the molecular mechanisms underlying vesicle trafficking to the equatorial site and how this process is coupled with the dynamics of the contractile apparatus are poorly defined. Here we provide evidence for the requirement of Rab1 during cleavage furrow ingression in cytokinesis. We demonstrate that the gene omelette ( omt ) encodes the Drosophila orthologue of human Rab1 and is required for successful cytokinesis in both mitotic and meiotic dividing cells of Drosophila melanogaster . We show that Rab1 protein colocalizes with the conserved oligomeric Golgi (COG) complex Cog7 subunit and the phosphatidylinositol 4-phosphate effector GOLPH3 at the Golgi stacks. Analysis by transmission electron microscopy and 3D-SIM super-resolution microscopy reveals loss of normal Golgi architecture in omt mutant spermatocytes indicating a role for Rab1 in Golgi formation. In dividing cells, Rab1 enables stabilization and contraction of actomyosin rings. We further demonstrate that GTP-bound Rab1 directly interacts with GOLPH3 and controls its localization at the Golgi and at the cleavage site . We propose that Rab1, by associating with GOLPH3, controls membrane trafficking and contractile ring constriction during cytokinesis.

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