scholarly journals A stitch in time: Replicate early and escape dosage compensation to express more

2017 ◽  
Vol 216 (7) ◽  
pp. 1869-1870
Author(s):  
María Gómez
Keyword(s):  
Dosage Compensation ◽  
Biological Significance ◽  
Replication Timing ◽  
Expression Levels ◽  
Cell Biol ◽  
Early Replication ◽  
Eukaryotic Genomes

The biological significance of conserved replication timing patterns in eukaryotic genomes remains a mystery. In this issue, Müller and Nieduszynski (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701061) find that early replication is a requirement for the highest expression levels of certain genes.

scholarly journals DNA replication timing influences gene expression level

2017 ◽  
Vol 216 (7) ◽  
pp. 1907-1914 ◽  
Author(s):  
Carolin A. Müller ◽  
Conrad A. Nieduszynski
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Temporal Order ◽  
Yeast Species ◽  
Replication Timing ◽  
Histone Genes ◽  
Cell Cycle Genes ◽  
Compensation Mechanisms ◽  
Dna Replication Timing ◽  
Eukaryotic Genomes

Eukaryotic genomes are replicated in a reproducible temporal order; however, the physiological significance is poorly understood. We compared replication timing in divergent yeast species and identified genomic features with conserved replication times. Histone genes were among the earliest replicating loci in all species. We specifically delayed the replication of HTA1-HTB1 and discovered that this halved the expression of these histone genes. Finally, we showed that histone and cell cycle genes in general are exempt from Rtt109-dependent dosage compensation, suggesting the existence of pathways excluding specific loci from dosage compensation mechanisms. Thus, we have uncovered one of the first physiological requirements for regulated replication time and demonstrated a direct link between replication timing and gene expression.

Dispersed Repetitive Sequences in Eukaryotic Genomes and Their Possible Biological Significance

1983 ◽  
Vol 47 (0) ◽  
pp. 1109-1121 ◽  
Author(s):  
G.P. Georgiev ◽  
D.A. Kramerov ◽  
A.P. Ryskov ◽  
K.G. Skryabin ◽  
E.M. Lukanidin
Keyword(s):  
Repetitive Sequences ◽  
Biological Significance ◽  
Eukaryotic Genomes

scholarly journals Finding a Balance: How Diverse Dosage Compensation Strategies Modify Histone H4 to Regulate Transcription

2012 ◽  
Vol 2012 ◽  
pp. 1-12
Author(s):  
Michael B. Wells ◽  
Györgyi Csankovszki ◽  
Laura M. Custer
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Current Understanding ◽  
Histone H4 ◽  
Linked Gene ◽  
Expression Levels ◽  
Gene Expression Levels

Dosage compensation balances gene expression levels between the sex chromosomes and autosomes and sex-chromosome-linked gene expression levels between the sexes. Different dosage compensation strategies evolved in different lineages, but all involve changes in chromatin. This paper discusses our current understanding of how modifications of the histone H4 tail, particularly changes in levels of H4 lysine 16 acetylation and H4 lysine 20 methylation, can be used in different contexts to either modulate gene expression levels twofold or to completely inhibit transcription.

scholarly journals Local rewiring of genome - nuclear lamina interactions by transcription

2019 ◽  
Author(s):  
Laura Brueckner ◽  
Peiyao A Zhao ◽  
Tom van Schaik ◽  
Christ Leemans ◽  
Jiao Sima ◽  
...  
Keyword(s):  
Detailed Analysis ◽  
Gene Loss ◽  
Nuclear Lamina ◽  
Replication Timing ◽  
Transcription Unit ◽  
Nuclear Interior ◽  
It Impacts ◽  
Early Replication ◽  
Inactive Genes ◽  
Systematic Manipulation

AbstractTranscriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina-associated domains (LADs). Activation of such genes is often accompanied by repositioning towards the nuclear interior. How this process works and how it impacts flanking chromosomal regions is poorly understood. We addressed these questions by systematic manipulation of gene activity and detailed analysis of NL interactions. Activation of genes inside LADs typically causes detachment of the entire transcription unit but rarely more than 50-100 kb of flanking DNA, even when multiple neighboring genes are activated. The degree of detachment depends on the expression level and the length of the activated gene. Loss of NL interactions coincides with a switch from late to early replication timing, but the latter can involve longer stretches of DNA. These findings show how NL interactions can be shaped locally by transcription and point to a remarkable flexibility of interphase chromosomes.

scholarly journals Replication timing maintains the global epigenetic state in human cells

2019 ◽  
Author(s):  
Kyle N. Klein ◽  
Peiyao A. Zhao ◽  
Xiaowen Lyu ◽  
Daniel A. Bartlett ◽  
Amar Singh ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Cancer Cell Line ◽  
Replication Timing ◽  
Cell Types ◽  
Control Factor ◽  
Epigenetic State ◽  
Genome Wide ◽  
A Genome ◽  
A Cell ◽  
Early Replication

AbstractDNA is replicated in a defined temporal order termed the replication timing (RT) program. RT is spatially segregated in the nucleus with early/late replication corresponding to Hi-C A/B chromatin compartments, respectively. Early replication is also associated with active histone modifications and transcriptional permissiveness. However, the mechanistic interplay between RT, chromatin state, and genome compartmentalization is largely unknown. Here we report that RT is central to epigenome maintenance and compartmentalization in both human embryonic stem cells (hESCs) and cancer cell line HCT116. Knockout (KO) of the conserved RT control factor RIF1, rather than causing discrete RT switches as previously suspected, lead to dramatically increased cell to cell heterogeneity of RT genome wide, despite RIF1’s enrichment in late replicating chromatin. RIF1 KO hESCs have a nearly random RT program, unlike all prior RIF1 KO cells, including HCT116, which show localized alterations. Regions that retain RT, which are prevalent in HCT116 but rare in hESCs, consist of large H3K9me3 domains revealing two independent mechanisms of RT regulation that are used to different extents in different cell types. RIF1 KO results in a striking genome wide downregulation of H3K27ac peaks and enrichment of H3K9me3 at large domains that remain late replicating, while H3K27me3 and H3K4me3 are re-distributed genome wide in a cell type specific manner. These histone modification changes coincided with global reorganization of genome compartments, transcription changes and a genome wide strengthening of TAD structures. Inducible degradation of RIF1 revealed that disruption of RT is upstream of genome compartmentalization changes. Our findings demonstrate that disruption of RT leads to widespread epigenetic mis-regulation, supporting previously speculative models in which the timing of chromatin assembly at the replication fork plays a key role in maintaining the global epigenetic state, which in turn drives genome architecture.

scholarly journals Replication dynamics of individual loci in single living cells reveal variation of stochasticity

2018 ◽  
Author(s):  
Bénédicte Duriez ◽  
Sabarinadh Chilaka ◽  
Jean-François Bercher ◽  
Eslande Hercul ◽  
Nicole Boggetto ◽  
...  
Keyword(s):  
Replication Timing ◽  
S Phase ◽  
Timing Control ◽  
Homologous Chromosomes ◽  
Stochastic Nature ◽  
Time Period ◽  
Single Living Cells ◽  
Phase Out ◽  
Single Living ◽  
Eukaryotic Genomes

AbstractEukaryotic genomes are replicated under the control of a highly sophisticated program during the restricted time period corresponding to S-phase. The most widely used replication timing assays, which are performed on populations of millions of cells, suggest that most of the genome is synchronously replicated on homologous chromosomes. We investigated the stochastic nature of this temporal program, by comparing the precise replication times of allelic loci within single vertebrate cells progressing through S-phase at six loci replicated from very early to very late. We show that replication timing is strictly controlled for the three loci replicated in the first half of S-phase. Out of the three loci replicated in the second part of S-phase, two present a significantly more stochastic pattern. Surprisingly, we find that the locus replicated at the very end of S-phase, presents stochasticity similar to those replicated in early S-phase. We suggest that the richness of loci in efficient origins of replication, which decreases from early-to late-replicating regions, may underlie the variation of timing control during S-phase.

scholarly journals Camptothecin-Induced Replication Stress Affects DNA Replication Profiling by E/L Repli-Seq

2021 ◽  
pp. 1-8
Author(s):  
Takuya Hayakawa ◽  
Rino Suzuki ◽  
Kazuhiro Kagotani ◽  
Katsuzumi Okumura ◽  
Shin-ichiro Takebayashi
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Topoisomerase I ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Replication Timing ◽  
Replication Stress ◽  
Replication Initiation ◽  
Domain Structures ◽  
Early Replication

E/L Repli-seq is a powerful tool for detecting cell type-specific replication landscapes in mammalian cells, but its potential to monitor DNA replication under replication stress awaits better understanding. Here, we used E/L Repli-seq to examine the temporal order of DNA replication in human retinal pigment epithelium cells treated with the topoisomerase I inhibitor camptothecin. We found that the replication profiles by E/L Repli-seq exhibit characteristic patterns after replication-stress induction, including the loss of specific initiation zones within individual early replication timing domains. We also observed global disappearance of the replication timing domain structures in the profiles, which can be explained by checkpoint-dependent suppression of replication initiation. Thus, our results demonstrate the effectiveness of E/L Repli-seq at identifying cells with replication-stress-induced altered DNA replication programs.

scholarly journals Functional differences between L- and T-plastin isoforms.

1994 ◽  
Vol 127 (6) ◽  
pp. 1995-2008 ◽  
Author(s):  
M Arpin ◽  
E Friederich ◽  
M Algrain ◽  
F Vernel ◽  
D Louvard
Keyword(s):  
Cell Line ◽  
Tissue Specificity ◽  
Cell Function ◽  
Biological Significance ◽  
Epithelial Cell Line ◽  
Functional Differences ◽  
Cell Biol ◽  
Ionic Detergent ◽  
A Cell ◽  
Cell Type Specific

Fimbrins/plastins are a family of highly conserved actin-bundling proteins. They are present in all eukaryotic cells including yeast, but each isoform displays a remarkable tissue specificity. T-plastin is normally found in epithelial and mesenchymal cells while L-plastin is present in hematopoietic cells. However, L-plastin has been also found in tumor cells of non-hematopoietic origin (Lin, C.-S., R. H. Aebersold, S. B. Kent, M. Varma, and J. Leavitt. 1988. Mol. Cell. Biol. 8:4659-4668; Lin, C.-S., R. H. Aebersold, and J. Leavitt. 1990. Mol. Cell. Biol. 10: 1818-1821). To learn more about the biological significance of their tissue specificity, we have overproduced the T- and L-plastin isoforms in a fibroblast-like cell line, CV-1, and in a polarized epithelial cell line, LLC-PK1. In CV-1 cells, overproduction of T- and L-plastins induces cell rounding and a concomitant reorganization of actin stress fibers into geodesic structures. L-plastin remains associated with microfilaments while T-plastin is almost completely extracted after treatment of the cells with non-ionic detergent. In LLC-PK1 cells, T-plastin induces shape changes in microvilli and remains associated with microvillar actin filaments after detergent extraction while L-plastin has no effect on these structures and is completely extracted. The effect of T-plastin on the organization of microvilli differs from that of villin, another actin-bundling protein. Our experiments indicate that these two isoforms play differing roles in actin filament organization, and do so in a cell type-specific fashion. Thus it is likely that these plastin isoforms play fundamentally different roles in cell function.

Receptor tyrosine kinases and growth factors expression in tumor thrombus cells in patients with renal cell carcinoma (RCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17073-e17073
Author(s):  
Maria Volkova ◽  
Ilya Tsimafeyeu ◽  
Dmitry Khochenkov ◽  
Anna Olshanskaia ◽  
Niko Vashakmadze ◽  
...  
Keyword(s):  
Growth Factors ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tyrosine Kinases ◽  
Tumor Thrombus ◽  
Receptor Tyrosine Kinases ◽  
Detection System ◽  
Biological Significance ◽  
Expression Levels ◽  
Lower Expression

e17073 Background: To our knowledge, this is a first study describing the expression of the receptor tyrosine kinases (RTKs) and growth factors (GFs) in venous tumor thrombus cells and comparing results with the expression in primary RCC. Methods: Formalin-fixed paraffin-embedded specimens of tumor thrombus and primary tumor removed from 25 untreated pT3a-T4N0-1M0-1 RCC patients were evaluated by immunohistochemistry with primary antibodies to VEGF-A, FGF2, VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRα, and PDGFRβ (Abcam/Santa Cruz Biotech) and REAL™ EnVision™ Detection System (Agilent). The extent of expression was compared with 25 specimens of primary tumor tissue (selected from the same patients). Significant differences in the expression among these groups were assessed by chi-squared and Fisher's exact tests using a semi-quantitative method (H-score). The analysis of the correlation between expression levels and RCC characteristics was also performed. Results: Mean age was 62.0 (35-74) years. pT3a, pT3b, pT3c and pT4 stages were detected in 4 (16.0%), 13 (52.0%), 7 (28.0%), and 1 (4.0%) patients. Lymph node metastases were found in 9 (36.0%) cases, 15 (60.0%) patients had 1 or more metastatic sites. All RTKs and GFs were heavily expressed in primary tumor cells. Tumor thrombus cells were characterized by significant lower expression levels of VEGFR1, VEGFR2, and PDGFRα (p < 0.05 for all). Tendency to lower expression of VEGF-A (p = 0.06), FGF-2 (p = 0.046), FGFR1 (p = 0.077), and FGFR2 (p = 0.09) was observed in tumor thrombus cells (Table). VEGFR2 expression levels were 2-times reduced in patients with supradiaphragmatic thrombus (H-score = 21.4±12.0) compared to infradiaphragmatic thrombus (H-score = 55.0±8.5, p = 0.042). Furman grade correlated with the expression levels of VEGFR1 (p = 0.035) and FGFR1 (p = 0.022) in primary tumor cells; tumor invasion into venous wall correlated with the expression levels of VEGFR1 (p = 0.023) and FGFR2 (p = 0.005) in thrombus cells. Conclusions: RCC invasion into veins is accompanied by a decrease in expression of RTKs and GFs. Further studies are needed to understand the biological significance. [Table: see text]

scholarly journals Platforms for Investigating LncRNA Functions

2018 ◽  
Vol 23 (6) ◽  
pp. 493-506 ◽  
Author(s):  
John Lalith Charles Richard ◽  
Pieter Johan Adam Eichhorn
Keyword(s):  
Next Generation Sequencing ◽  
Dosage Compensation ◽  
Messenger Rna ◽  
Noncoding Rnas ◽  
Rna Degradation ◽  
Biological Processes ◽  
Protein Kinetics ◽  
Heterogeneous Nature ◽  
Eukaryotic Genomes ◽  
Generation Sequencing

Prior to the sequencing of the human genome, it was presumed that most of the DNA coded for proteins. However, with the advent of next-generation sequencing, it has now been recognized that most complex eukaryotic genomes are in fact transcribed into noncoding RNAs (ncRNAs), including a family of transcripts referred to as long noncoding RNAs (lncRNAs). LncRNAs have been implicated in many biological processes ranging from housekeeping functions such as transcription to more specialized functions such as dosage compensation or genomic imprinting, among others. Interestingly, lncRNAs are not limited to a defined set of functions but can regulate varied activities such as messenger RNA degradation, translation, and protein kinetics or function as RNA decoys or scaffolds. Although still in its infancy, research into the biology of lncRNAs has demonstrated the importance of lncRNAs in development and disease. However, the specific mechanisms through which these lncRNAs act remain poorly defined. Focused research into a small number of these lncRNAs has provided important clues into the heterogeneous nature of this family of ncRNAs. Due to the complex diversity of lncRNA function, in this review, we provide an update on the platforms available for investigators to aid in the identification of lncRNA function.

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