scholarly journals A Tale of Two States: Pluripotency Regulation of Telomeres

2021 ◽  
Vol 9 ◽  
Author(s):  
Clara Lopes Novo
Keyword(s):  
Phase Separation ◽  
Genome Stability ◽  
Chromosome Instability ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
3D Genome ◽  
Cellular Processes ◽  
Damage Repair ◽  
Dimensional Network ◽  
Telomere Regulation

Inside the nucleus, chromatin is functionally organized and maintained as a complex three-dimensional network of structures with different accessibility such as compartments, lamina associated domains, and membraneless bodies. Chromatin is epigenetically and transcriptionally regulated by an intricate and dynamic interplay of molecular processes to ensure genome stability. Phase separation, a process that involves the spontaneous organization of a solution into separate phases, has been proposed as a mechanism for the timely coordination of several cellular processes, including replication, transcription and DNA repair. Telomeres, the repetitive structures at the end of chromosomes, are epigenetically maintained in a repressed heterochromatic state that prevents their recognition as double-strand breaks (DSB), avoiding DNA damage repair and ensuring cell proliferation. In pluripotent embryonic stem cells, telomeres adopt a non-canonical, relaxed epigenetic state, which is characterized by a low density of histone methylation and expression of telomere non-coding transcripts (TERRA). Intriguingly, this telomere non-canonical conformation is usually associated with chromosome instability and aneuploidy in somatic cells, raising the question of how genome stability is maintained in a pluripotent background. In this review, we will explore how emerging technological and conceptual developments in 3D genome architecture can provide novel mechanistic perspectives for the pluripotent epigenetic paradox at telomeres. In particular, as RNA drives the formation of LLPS, we will consider how pluripotency-associated high levels of TERRA could drive and coordinate phase separation of several nuclear processes to ensure genome stability. These conceptual advances will provide a better understanding of telomere regulation and genome stability within the highly dynamic pluripotent background.

scholarly journals The Fission Yeast Rad32 (Mre11)-Rad50-Nbs1 Complex Is Required for the S-Phase DNA Damage Checkpoint

2003 ◽  
Vol 23 (18) ◽  
pp. 6564-6573 ◽  
Author(s):  
Charly Chahwan ◽  
Toru M. Nakamura ◽  
Sasirekha Sivakumar ◽  
Paul Russell ◽  
Nicholas Rhind
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Chromosome Instability ◽  
S Phase ◽  
Comparative Genomic ◽  
Dna Damage Checkpoint ◽  
Checkpoint Signaling ◽  
Damage Repair ◽  
Genomic Approach ◽  
Telomere Regulation

ABSTRACT Mre11, Rad50, and Nbs1 form a conserved heterotrimeric complex that is involved in recombination and DNA damage checkpoints. Mutations in this complex disrupt the S-phase DNA damage checkpoint, the checkpoint which slows replication in response to DNA damage, and cause chromosome instability and cancer in humans. However, how these proteins function and specifically where they act in the checkpoint signaling pathway remain crucial questions. We identified fission yeast Nbs1 by using a comparative genomic approach and showed that the genes for human Nbs1 and fission yeast Nbs1 and that for their budding yeast counterpart, Xrs2, are members of an evolutionarily related but rapidly diverging gene family. Fission yeast Nbs1, Rad32 (the homolog of Mre11), and Rad50 are involved in DNA damage repair, telomere regulation, and the S-phase DNA damage checkpoint. However, they are not required for G2 DNA damage checkpoint. Our results suggest that a complex of Rad32, Rad50, and Nbs1 acts specifically in the S-phase branch of the DNA damage checkpoint and is not involved in general DNA damage recognition or signaling.

scholarly journals At the Crossroad of Gene Regulation and Genome Organization: Potential Roles for ATP-Dependent Chromatin Remodelers in the Regulation of CTCF-Mediated 3D Architecture

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 272
Author(s):  
Aktan Alpsoy ◽  
Surbhi Sood ◽  
Emily C. Dykhuizen
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Chromatin Remodelers ◽  
3D Genome ◽  
Quiescent Cells ◽  
Damage Repair ◽  
Architectural Proteins ◽  
3D Architecture ◽  
Specific Factors ◽  
Hierarchical Folding

In higher order organisms, the genome is assembled into a protein-dense structure called chromatin. Chromatin is spatially organized in the nucleus through hierarchical folding, which is tightly regulated both in cycling cells and quiescent cells. Assembly and folding are not one-time events in a cell’s lifetime; rather, they are subject to dynamic shifts to allow changes in transcription, DNA replication, or DNA damage repair. Chromatin is regulated at many levels, and recent tools have permitted the elucidation of specific factors involved in the maintenance and regulation of the three-dimensional (3D) genome organization. In this review/perspective, we aim to cover the potential, but relatively unelucidated, crosstalk between 3D genome architecture and the ATP-dependent chromatin remodelers with a specific focus on how the architectural proteins CTCF and cohesin are regulated by chromatin remodeling.

scholarly journals Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Dan-Ya Wu ◽  
Xinxin Li ◽  
Qiao-Ran Sun ◽  
Cheng-Li Dou ◽  
Tian Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Somatic Cell ◽  
Genome Organization ◽  
Nuclear Transfer ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Differentiation Potential ◽  
3D Genome

AbstractNuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.

scholarly journals Three-dimensional organization of chromatin associated RNAs and their role in chromatin architecture in human cells

2021 ◽  
Author(s):  
Riccardo Calandrelli ◽  
Xingzhao Wen ◽  
Tri C. Nguyen ◽  
Chien-Ju Chen ◽  
Zhijie Qi ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Chromatin Loops ◽  
3D Genome ◽  
Vital Component ◽  
Genome Interactions ◽  
Global Reduction

Chromatin-associated RNA (caRNA) is a vital component of the interphase nucleus; yet its distribution and role in the 3D genome organization remain poorly understood. Here, we map caRNA's spatial distribution on the 3D genome in human embryonic stem cells, fibroblasts, and myelogenous leukemia cells. We find that the relative abundance of trans-acting caRNA on DNA reflects the 3D compartmentalization, and the caRNA's sequence is predictive of its spatial localization. We observe localized caRNA-genome interactions that span several hundred kilobases to several megabases. These caRNA domains correlate with chromatin loops and enhancer-promoter interactions. Global reduction of caRNA abundance increases the number of chromatin loops and strengths, which could be reversed by suppression of caRNA's electrostatic interactions. These results indicate that caRNA regulates chromatin looping, at least in part through RNA's electrostatic interactions.

scholarly journals Rice 3D chromatin structure correlates with sequence variation and meiotic recombination rate

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Agnieszka A. Golicz ◽  
Prem L. Bhalla ◽  
David Edwards ◽  
Mohan B. Singh
Keyword(s):  
Meiotic Recombination ◽  
Recombination Rate ◽  
Sequence Variation ◽  
Genome Structure ◽  
Rice Genome ◽  
Three Dimensional ◽  
3D Genome ◽  
Cellular Processes ◽  
Eukaryotic Species ◽  
Topologically Associated Domains

AbstractGenomes of many eukaryotic species have a defined three-dimensional architecture critical for cellular processes. They are partitioned into topologically associated domains (TADs), defined as regions of high chromatin inter-connectivity. While TADs are not a prominent feature of A. thaliana genome organization, they have been reported for other plants including rice, maize, tomato and cotton and for which TAD formation appears to be linked to transcription and chromatin epigenetic status. Here we show that in the rice genome, sequence variation and meiotic recombination rate correlate with the 3D genome structure. TADs display increased SNP and SV density and higher recombination rate compared to inter-TAD regions. We associate the observed differences with the TAD epigenetic landscape, TE composition and an increased incidence of meiotic crossovers.

scholarly journals Epigenomic and 3D genome architecture in naïve and primed human embryonic stem cell states

2017 ◽  
Author(s):  
Stephanie L. Battle ◽  
Naresh Doni Jayavelu ◽  
Robert N. Azad ◽  
Jennifer Hesson ◽  
Faria N. Ahmed ◽  
...  
Keyword(s):  
Human Embryonic Stem Cell ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Genome Architecture ◽  
Open Chromatin ◽  
Substantial Portion ◽  
3D Genome ◽  
Mammalian Embryogenesis ◽  
Post Implantation ◽  
Epigenomic Reprogramming

ABSTRACTDuring mammalian embryogenesis changes in morphology and gene expression are concurrent with epigenomic reprogramming. Using human embryonic stem cells representing the pre-implantation blastocyst (naïve) and post-implantation epiblast (primed), our data demonstrate that a substantial portion of known human enhancers are pre-marked by H3K4me1 in naïve cells, providing an enhanced open chromatin state in naïve pluripotency. The naïve enhancer repertoire occupies nine percent of the genome, three times that of primed cells, and can exist in broad chromatin domains over fifty kilobases. Enhancer chromatin states are largely poised. Seventy-seven percent of naïve enhancers are decommissioned in a stepwise manner as cells become primed. While primed topological associated domains are unaltered upon differentiation, naïve domains expand across primed boundaries, impacting three dimensional genome architecture. Differential topological associated domain edges coincide with naïve H3K4me1 enrichment. Our results suggest that naïve-derived cells have a chromatin landscape reflective of early embryogenesis.

scholarly journals Poly-Epsilon-Lysine Hydrogels with Dynamic Crosslinking Facilitates Cell Proliferation

Materials ◽  
2020 ◽  
Vol 13 (17) ◽  
pp. 3851
Author(s):  
Nestor Lopez Mora ◽  
Matthew Owens ◽  
Sara Schmidt ◽  
Andreia F. Silva ◽  
Mark Bradley
Keyword(s):  
Biomedical Applications ◽  
Cell Attachment ◽  
Three Dimensional ◽  
Cellular Migration ◽  
Cellular Processes ◽  
Dimensional Network ◽  
Proliferation And Differentiation ◽  
Cell Processes ◽  
Arginine Glycine Aspartic Acid ◽  
Imine Bond

The extracellular matrix (ECM) is a three-dimensional network within which fundamental cell processes such as cell attachment, proliferation, and differentiation occur driven by its inherent biological and structural cues. Hydrogels have been used as biomaterials as they possess many of the ECM characteristics that control cellular processes. However, the permanent crosslinking often found in hydrogels fails to recapitulate the dynamic nature of the natural ECM. This not only hinders natural cellular migration but must also limit cellular expansion and growth. Moreover, there is an increased interest in the use of new biopolymers to create biomimetic materials that can be used for biomedical applications. Here we report on the natural polymer poly-ε-lysine in forming dynamic hydrogels via reversible imine bond formation, with cell attachment promoted by arginine-glycine-aspartic acid (RGD) incorporation. Together, the mechanical properties and cell behavior of the dynamic hydrogels with low poly-ε-lysine quantities indicated good cell viability and high metabolic activity.

scholarly journals Histone Modifications and Other Facets of Epigenetic Regulation in Trypanosomatids: Leaving Their Mark

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Swati Saha
Keyword(s):  
Histone Modifications ◽  
Epigenetic Regulation ◽  
Posttranslational Modifications ◽  
High Resolution Mass Spectrometry ◽  
Three Dimensional ◽  
Early Years ◽  
Host Immune System ◽  
3D Genome ◽  
Cellular Processes ◽  
The Impact

ABSTRACT Histone posttranslational modifications (PTMs) modulate several eukaryotic cellular processes, including transcription, replication, and repair. Vast arrays of modifications have been identified in conventional eukaryotes over the last 20 to 25 years. While initial studies uncovered these primarily on histone tails, multiple modifications were subsequently found on the central globular domains as well. Histones are evolutionarily conserved across eukaryotes, and a large number of their PTMs and the functional relevance of these PTMs are largely conserved. Trypanosomatids, however, are early diverging eukaryotes. Although possessing all four canonical histones as well as several variants, their sequences diverge from those of other eukaryotes, particularly in the tails. Consequently, the modifications they carry also vary. Initial analyses almost 15 years ago suggested that trypanosomatids possessed a smaller collection of histone modifications. However, exhaustive high resolution mass spectrometry analyses in the last few years have overturned this belief, and it is now evident that the “histone code” proposed by Allis and coworkers in the early years of this century is as complex in these organisms as in other eukaryotes. Trypanosomatids cause several diseases, and the members of this group of organisms have varied lifestyles, evolving diverse mechanisms to evade the host immune system, some of which have been found to be principally controlled by epigenetic mechanisms. This minireview aims to acquaint the reader with the impact of histone PTMs on trypanosomatid cellular processes, as well as other facets of trypanosomatid epigenetic regulation, including the influence of three-dimensional (3D) genome architecture, and discusses avenues for future investigations.

scholarly journals PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice

2017 ◽  
Vol 37 (23) ◽  
Author(s):  
Ayako L. Mochizuki ◽  
Ami Katanaya ◽  
Eri Hayashi ◽  
Mihoko Hosokawa ◽  
Emiko Moribe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Genome Stability ◽  
Ex Vivo ◽  
Chromosome Instability ◽  
Embryonic Stem ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Origin Firing

ABSTRACT DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stability in vivo and ex vivo. Of note, Pari-deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice.

scholarly journals Systematic over-expression screens for chromosome instability identify conserved dosage chromosome instability genes in yeast and human tumors

2016 ◽  
Author(s):  
Supipi Duffy ◽  
Hok Khim Fam ◽  
Yikan Wang ◽  
Erin B Styles ◽  
Jung-Huyn Kim ◽  
...  
Keyword(s):  
Genome Stability ◽  
Target Genes ◽  
Chromosome Instability ◽  
Model Organisms ◽  
Genetic Screens ◽  
Over Expression ◽  
Damage Repair ◽  
Candidate Target ◽  
Yeast Genes

Somatic copy number amplifications (SCNAs) and gene over-expression are common features of many cancers. To determine the role of gene over-expression on genome stability, we performed functional genomic screens in the budding yeast for chromosome instability, a defining characteristic of cancer that can be targeted by therapeutics. Over-expression of 245 yeast genes increases chromosome instability by influencing processes such as chromosome segregation and DNA damage repair. Testing candidate human homologs, which were highly recurrently altered in tumors lead to the identification of 2 genes, Tdp1 and Taf12 that contribute to CIN in human cells when over-expressed. Rhabdomyosarcoma lines with higher levels of Tdp1 also show chromosome instability and can be partially rescued by siRNA-mediated knockdown of Tdp1. Using synthetic dosage lethality screens in yeast, we identified candidate target genes that will specifically target tumors with high levels of Tdp1. We demonstrate the utility of functional genetic screens in model organisms to broaden the spectrum of CIN genes, to identify novel genes relevant to chromosome instability in humans and to identify candidate gene targets that can be leveraged to selectively kill tumors over-expressing specific genes.

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