scholarly journals Genome reconfiguration prior to mitosis shapes the generation of adaptive immunity

2019 ◽  
Author(s):  
Wing Fuk Chan ◽  
Hannah D. Coughlan ◽  
Jie H.S. Zhou ◽  
Christine R. Keenan ◽  
Naiara G. Bediaga ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cellular Differentiation ◽  
Plasma Cells ◽  
Control Cell ◽  
Quiescent State ◽  
Chromosome Conformation ◽  
Genome Reorganization ◽  
Gene Regulatory ◽  
Second Wave ◽  
Control Cell Differentiation

AbstractDuring cellular differentiation chromosome conformation is altered to support the lineage-specific transcriptional programs required for cell identity. When these changes occur in relation to cell cycle, division and time is unclear. Here we followed B lymphocytes as they differentiated from a naïve, quiescent state into antibody secreting plasma cells. Unexpectedly, we found that gene-regulatory chromosome reorganization occurred prior to the first division, in late G1 phase and that this configuration is maintained as the cells rapidly cycle during clonal expansion. A second wave of architectural changes also occurred later as cells differentiated into plasma cells and this was associated with increased time in G1 phase. These data provide an explanation for how lymphocyte fate is imprinted prior to the first division and suggest that chromosome reconfiguration is spatiotemporally separated from DNA replication and mitosis to ensure the implementation of a gene regulatory program that controls the differentiation process required for the generation of immunity.One Sentence SummaryDiscrete waves of genome reorganization, spatiotemporally separated from DNA replication and mitosis, control cell differentiation.

scholarly journals Pre-mitotic genome re-organisation bookends the B cell differentiation process

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wing Fuk Chan ◽  
Hannah D. Coughlan ◽  
Jie H. S. Zhou ◽  
Christine R. Keenan ◽  
Naiara G. Bediaga ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Plasma Cells ◽  
G1 Phase ◽  
Quiescent State ◽  
Differentiation Process ◽  
B Cell Differentiation ◽  
Chromosome Conformation ◽  
Cellular Activation ◽  
Expression Program ◽  
Second Wave

AbstractDuring cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity.

scholarly journals Shelterin components mediate genome reorganization in response to replication stress

2017 ◽  
Vol 114 (21) ◽  
pp. 5479-5484 ◽  
Author(s):  
Takeshi Mizuguchi ◽  
Nitika Taneja ◽  
Emiko Matsuda ◽  
Jon-Matthew Belton ◽  
Peter FitzGerald ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Organization ◽  
Genome Stability ◽  
Regulation Of Gene Expression ◽  
Replication Stress ◽  
Yeast Cells ◽  
Chromosome Conformation ◽  
Genome Reorganization ◽  
Damage Repair ◽  
Telomere Protection

The dynamic nature of genome organization impacts critical nuclear functions including the regulation of gene expression, replication, and DNA damage repair. Despite significant progress, the mechanisms responsible for reorganization of the genome in response to cellular stress, such as aberrant DNA replication, are poorly understood. Here, we show that fission yeast cells carrying a mutation in the DNA-binding protein Sap1 show defects in DNA replication progression and genome stability and display extensive changes in genome organization. Chromosomal regions such as subtelomeres that show defects in replication progression associate with the nuclear envelope in sap1 mutant cells. Moreover, high-resolution, genome-wide chromosome conformation capture (Hi-C) analysis revealed prominent contacts between telomeres and chromosomal arm regions containing replication origins proximal to binding sites for Taz1, a component of the Shelterin telomere protection complex. Strikingly, we find that Shelterin components are required for interactions between Taz1-associated chromosomal arm regions and telomeres. These analyses reveal an unexpected role for Shelterin components in genome reorganization in cells experiencing replication stress, with important implications for understanding the mechanisms governing replication and genome stability.

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.

Cellular Differentiation in Response to Nutrient Availability: The Repressor of Meiosis, Rme1p, Positively Regulates Invasive Growth in Saccharomyces cerevisiae

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1045-1058
Author(s):  
Dewald van Dyk ◽  
Guy Hansson ◽  
Isak S Pretorius ◽  
Florian F Bauer
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cellular Differentiation ◽  
Promoter Sequence ◽  
Quiescent State ◽  
Invasive Growth ◽  
Limited Growth ◽  
Yeast Saccharomyces Cerevisiae ◽  
A Cell ◽  
Signaling Modules ◽  
Differentiation Pathways

Abstract In the yeast Saccharomyces cerevisiae, the transition from a nutrient-rich to a nutrient-limited growth medium typically leads to the implementation of a cellular adaptation program that results in invasive growth and/or the formation of pseudohyphae. Complete depletion of essential nutrients, on the other hand, leads either to entry into a nonbudding, metabolically quiescent state referred to as G0 in haploid strains or to meiosis and sporulation in diploids. Entry into meiosis is repressed by the transcriptional regulator Rme1p, a zinc-finger-containing DNA-binding protein. In this article, we show that Rme1p positively regulates invasive growth and starch metabolism in both haploid and diploid strains by directly modifying the transcription of the FLO11 (also known as MUC1) and STA2 genes, which encode a cell wall-associated protein essential for invasive growth and a starch-degrading glucoamylase, respectively. Genetic evidence suggests that Rme1p functions independently of identified signaling modules that regulate invasive growth and of other transcription factors that regulate FLO11 and that the activation of FLO11 is dependent on the presence of a promoter sequence that shows significant homology to identified Rme1p response elements (RREs). The data suggest that Rme1p functions as a central switch between different cellular differentiation pathways.

scholarly journals COL2A1 Is a Novel Biomarker of Melanoma Tumor Repopulating Cells

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 360
Author(s):  
Bhavana Talluri ◽  
Kshitij Amar ◽  
Michael Saul ◽  
Tasnim Shireen ◽  
Vjollca Konjufca ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Line ◽  
Aerobic Glycolysis ◽  
Parental Control ◽  
Control Cell ◽  
Differentially Expressed Gene ◽  
Gene Clusters ◽  
Rna Seq ◽  
Novel Biomarkers ◽  
Gene Regulatory

Soft 3D-fibrin-gel selected tumor repopulating cells (TRCs) from the B16F1 melanoma cell line exhibit extraordinary self-renewal and tumor-regeneration capabilities. However, their biomarkers and gene regulatory features remain largely unknown. Here, we utilized the next-generation sequencing-based RNA sequencing (RNA-seq) technique to discover novel biomarkers and active gene regulatory features of TRCs. Systems biology analysis of RNA-seq data identified differentially expressed gene clusters, including the cell adhesion cluster, which subsequently identified highly specific and novel biomarkers, such as Col2a1, Ncam1, F11r, and Negr1. We validated the expression of these genes by real-time qPCR. The expression level of Col2a1 was found to be relatively low in TRCs but twenty-fold higher compared to the parental control cell line, thus making the biomarker very specific for TRCs. We validated the COL2A1 protein by immunofluorescence microscopy, showing a higher expression of COL2A1 in TRCs compared to parental control cells. KEGG pathway analysis showed the JAK/STAT, hypoxia, and Akt signaling pathways to be active in TRCs. Besides, the aerobic glycolysis pathway was found to be very active, indicating a typical Warburg Effect on highly tumorigenic cells. Together, our study revealed highly specific biomarkers and active cell signaling pathways of melanoma TRCs that can potentially target and neutralize TRCs.

Applying attractor dynamics to infer gene regulatory interactions involved in cellular differentiation

Biosystems ◽  
2017 ◽  
Vol 155 ◽  
pp. 29-41 ◽  
Author(s):  
Ahmadreza Ghaffarizadeh ◽  
Gregory J. Podgorski ◽  
Nicholas S. Flann
Keyword(s):  
Cellular Differentiation ◽  
Regulatory Interactions ◽  
Attractor Dynamics ◽  
Gene Regulatory

scholarly journals Interdependent regulation of stereotyped and stochastic photoreceptor fates in the fly eye

2019 ◽  
Author(s):  
Adam C. Miller ◽  
Elizabeth Urban ◽  
Eric L. Lyons ◽  
Tory G. Herman ◽  
Robert J. Johnston
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Gene Networks ◽  
Control Cell ◽  
Regulatory Mechanisms ◽  
Cell Fates ◽  
Feedback Mechanisms ◽  
Fate Specification ◽  
Gene Regulatory ◽  
Fly Eye

AbstractDiversification of neuronal subtypes often requires stochastic gene regulatory mechanisms. How stochastically expressed transcription factors interact with other regulators in gene networks to specify cell fates is poorly understood. The random mosaic of color-detecting R7 photoreceptor subtypes in Drosophila is controlled by the stochastic on/off expression of the transcription factor Spineless (Ss). In SsON R7s, Ss induces expression of Rhodopsin 4 (Rh4), whereas in SsOFF R7s, the absence of Ss allows expression of Rhodopsin 3 (Rh3). Here, we find that the transcription factor Runt, which is initially expressed in all R7s, activates expression of Spineless in a random subset of R7s. Later, as R7s develop, Ss negatively feeds back onto Runt to prevent repression of Rh4 and ensure proper fate specification. Together, stereotyped and stochastic regulatory inputs are integrated into feedforward and feedback mechanisms to control cell fate.

scholarly journals The histone subcode: poly(ADP‐ribose) polymerase‐1 (Parp‐1) and Parp‐2 control cell differentiation by regulating the transcriptional intermediary factor TIF1β and the heterochromatin protein HPlα

2008 ◽  
Vol 22 (11) ◽  
pp. 3853-3865 ◽  
Author(s):  
Delphine Quénet ◽  
Véronique Gasser ◽  
Laetitia Fouillen ◽  
Florence Cammas ◽  
Sarah Sanglier‐Cianferani ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Control Cell ◽  
Heterochromatin Protein ◽  
Parp 1 ◽  
Control Cell Differentiation
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