scholarly journals Chromosome-wide co-fluctuation of stochastic gene expression in mammalian cells

2019 ◽  
Author(s):  
Mengyi Sun ◽  
Jianzhi Zhang
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Three Dimensional ◽  
Sequencing Data ◽  
Chromatin Dynamics ◽  
Gene Expression Noise ◽  
Genes Encoding ◽  
The Face ◽  
Allele Specific ◽  
Genomic Scale

ABSTRACTGene expression is subject to stochastic noise, but to what extent and by which means such stochastic variations are coordinated among different genes are unclear. We hypothesize that neighboring genes on the same chromosome co-fluctuate in expression because of their common chromatin dynamics, and verify it at the genomic scale using allele-specific single-cell RNA-sequencing data of mouse cells. Unexpectedly, the co-fluctuation extends to genes that are over 60 million bases apart. We provide evidence that this long-range effect arises in part from chromatin co-accessibilities of linked loci attributable to three-dimensional proximity, which is much closer intra-chromosomally than inter-chromosomally. We further show that genes encoding components of the same protein complex tend to be chromosomally linked, likely resulting from natural selection for intracellular among-component dosage balance. These findings have implications for both the evolution of genome organization and optimal design of synthetic genomes in the face of gene expression noise.

Regulation of gene expression and cellular proliferation by histone H2A.ZThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 179-188 ◽  
Author(s):  
Amy Svotelis ◽  
Nicolas Gévry ◽  
Luc Gaudreau
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Cellular Proliferation ◽  
Replicative Senescence ◽  
Peer Review Process ◽  
Regulation Of Gene Expression ◽  
Histone Variants ◽  
Chromatin Dynamics ◽  
Cycle Arrest

The mammalian genome is organized into a structure of DNA and proteins known as chromatin. In general, chromatin presents a barrier to gene expression that is regulated by several pathways, namely by the incorporation of histone variants into the nucleosome. In yeast, H2A.Z is an H2A histone variant that is incorporated into nucleosomes as an H2A.Z/H2B dimer by the Swr1 complex and by the SRCAP and p400/Tip60 complexes in mammalian cells. H2A.Z has been associated with the poising of genes for transcriptional activation in the yeast model system, and is essential for development in higher eukaryotes. Recent studies in our laboratory have demonstrated a p400-dependent deposition of H2A.Z at the promoter of p21WAF1/CIP1, a consequence that prevents the activation of the gene by p53, thereby inhibiting p53-dependent replicative senescence, a form of cell-cycle arrest crucial in the prevention of carcinogenic transformation of cells. Moreover, H2A.Z is overexpressed in several different types of cancers, and its overexpression has been associated functionally with the proliferation state of cells. Therefore, we suggest that H2A.Z is an important regulator of gene expression, and its deregulation may lead to the increased proliferation of mammalian cells.

scholarly journals Synchronization of stochastic expressions drives the clustering of functionally related genes

2019 ◽  
Vol 5 (10) ◽  
pp. eaax6525 ◽  
Author(s):  
Haiqing Xu ◽  
Jing-Jing Liu ◽  
Zhen Liu ◽  
Ying Li ◽  
Yong-Su Jin ◽  
...  
Keyword(s):  
Biological Significance ◽  
Expression Ratio ◽  
Chromatin Dynamics ◽  
Gene Expression Noise ◽  
Consecutive Reactions ◽  
Manipulative Experiments ◽  
Genes Encoding ◽  
Stochastic Expression ◽  
Widespread Phenomenon ◽  
Eukaryotic Genomes

Functionally related genes tend to be chromosomally clustered in eukaryotic genomes even after the exclusion of tandem duplicates, but the biological significance of this widespread phenomenon is unclear. We propose that stochastic expression fluctuations of neighboring genes resulting from chromatin dynamics are more or less synchronized such that their expression ratio is more stable than that for unlinked genes. Consequently, chromosomal clustering could be advantageous when the expression ratio of the clustered genes needs to stay constant, for example, because of the accumulation of toxic compounds when this ratio is altered. Evidence from manipulative experiments on the yeast GAL cluster, comprising three chromosomally adjacent genes encoding enzymes catalyzing consecutive reactions in galactose catabolism, unequivocally supports this hypothesis and elucidates how disorder in one biological phenomenon—gene expression noise—could prompt the emergence of order in another—genome organization.

scholarly journals A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence

2008 ◽  
Vol 180 (1) ◽  
pp. 51-65 ◽  
Author(s):  
R. Ileng Kumaran ◽  
David L. Spector
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Genetic Locus ◽  
Nuclear Periphery ◽  
Three Dimensional ◽  
Nuclear Lamina ◽  
Time Lapse ◽  
Living Cells ◽  
Cell System ◽  
Transcriptional Induction

The peripheral nuclear lamina, which is largely but not entirely associated with inactive chromatin, is considered to be an important determinant of nuclear structure and gene expression. We present here an inducible system to target a genetic locus to the nuclear lamina in living mammalian cells. Using three-dimensional time-lapse microscopy, we determined that targeting of the locus requires passage through mitosis. Once targeted, the locus remains anchored to the nuclear periphery in interphase as well as in daughter cells after passage through a subsequent mitosis. Upon transcriptional induction, components of the gene expression machinery are recruited to the targeted locus, and we visualized nascent transcripts at the nuclear periphery. The kinetics of transcriptional induction at the nuclear lamina is similar to that observed at an internal nuclear region. This new cell system provides a powerful approach to study the dynamics of gene function at the nuclear periphery in living cells.

scholarly journals Mammalian gene expression variability is explained by underlying cell state

2019 ◽  
Author(s):  
Robert Foreman ◽  
Roy Wollman
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Qualitative Difference ◽  
Live Cells ◽  
Expression Variability ◽  
Cell State ◽  
Relative Contribution ◽  
Allele Specific ◽  
Poisson Limit ◽  
Transcriptional Bursting

AbstractGene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH) we measured the multivariate gene expression distribution of 150 genes related to Ca2+ signaling coupled with the dynamic Ca2+ response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca2+ response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.

scholarly journals Allele-specific single-cell RNA sequencing reveals different architectures of intrinsic and extrinsic gene expression noises

2019 ◽  
Author(s):  
Mengyi Sun ◽  
Jianzhi Zhang
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Intrinsic Noise ◽  
Mouse Fibroblast ◽  
Extrinsic Noise ◽  
Gene Expression Noise ◽  
Cell State ◽  
Single Cell Rna Sequencing ◽  
Allele Specific

ABSTRACTGene expression noise refers to the variation of the expression level of a gene among isogenic cells in the same environment, and has two sources: extrinsic noise arising from the disparity of the cell state and intrinsic noise arising from the stochastic process of gene expression in the same cell state. Due to the low throughput of the existing method for measuring the two noise components, the architectures of intrinsic and extrinsic expression noises remain elusive. Using allele-specific single-cell RNA sequencing, we here estimate the two noise components of 3975 genes in mouse fibroblast cells. Our analyses verify predicted influences of several factors such as the TATA-box and microRNA targeting on intrinsic and extrinsic noises and reveal gene function-associated noise trends implicating the action of natural selection. These findings unravel differential regulations, optimizations, and biological consequences of intrinsic and extrinsic noises and can aid the construction of desired synthetic circuits.

scholarly journals Detection of allele-specific gene expression on Next Generation Sequencing data

2012 ◽  
Vol 18 (B) ◽  
pp. 130
Author(s):  
Vladan Mijatovic ◽  
Luciano Xumerle ◽  
Alberto Ferrarini ◽  
Ilaria Iacobucci ◽  
Chiara Pighi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Next Generation Sequencing ◽  
Next Generation Sequencing Data ◽  
Specific Gene ◽  
Next Generation ◽  
Sequencing Data ◽  
Specific Gene Expression ◽  
Allele Specific ◽  
Generation Sequencing

scholarly journals Single cell transcriptomes reveal characteristics of miRNA in gene expression noise reduction

2018 ◽  
Author(s):  
Tao Hu ◽  
Lei Wei ◽  
Shuailin Li ◽  
Tianrun Cheng ◽  
Xuegong Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Mirna Expression ◽  
Transcriptional Activation ◽  
Expression Profiles ◽  
Mrna Level ◽  
Interaction Strength ◽  
Sequencing Data ◽  
Gene Expression Noise ◽  
Expression Noise

AbstractIsogenic cells growing in identical environments show cell-to-cell variations because of stochastic gene expression. The high level of variation or noise could disrupt robust gene expression and result in tremendous consequences on cell behaviors. In this work, we showed evidence that microRNAs (miRNAs) could reduce gene expression noise in mRNA level of mouse cells based on single-cell RNA-sequencing data analysis. We identified that miRNA expression level, number of targets, targets pool abundance and interaction strength of miRNA with its targets are the key features contributing to noise repression. MiRNAs tend to work together as cooperative sub-networks to repress target noise synergistically in a cell type specific manner. Using a physical model of post-transcriptional regulation, we demonstrated that the accelerated degradation with elevated transcriptional activation of miRNA target provides resistance to extrinsic fluctuations. Together, through the integration analysis of single-cell RNA and miRNA expression profiles. We demonstrated that miRNAs are important post-transcriptional regulators for reducing gene expression noise and conferring robustness to biological processes.

scholarly journals S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling

2020 ◽  
Vol 6 (51) ◽  
pp. eabc5629
Author(s):  
Carolina Magdalen Greco ◽  
Marlene Cervantes ◽  
Jean-Michel Fustin ◽  
Kakeru Ito ◽  
Nicholas Ceglia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Mammalian Cells ◽  
Cellular Metabolism ◽  
Circadian Gene ◽  
Chromatin Dynamics ◽  
Pharmacological Inhibition ◽  
Genome Wide ◽  
Feedback Inhibitor ◽  
Transcription Activators

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)–dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

scholarly journals Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

2020 ◽  
Author(s):  
Sara H. Weitz ◽  
Jen Quick-Cleveland ◽  
Jose P. Jacob ◽  
Ian Barr ◽  
Rachel Senturia ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Rna Binding ◽  
Biological Significance ◽  
Culture Conditions ◽  
Sequencing Data ◽  
Mirna Sequencing ◽  
Typical Cell ◽  
Genomic Scale ◽  
In Cells

ABSTRACTThe essential biological cofactor heme is synthesized in cells in the Fe(II) form. Oxidized Fe(III) heme is specifically required for processing primary transcripts of microRNAs (pri-miRNAs) by the RNA-binding protein DGCR8, a core component of the Microprocessor complex. It is unknown how readily available Fe(III) heme is in the largely reducing environment in human cells and how changes in cellular Fe(III) heme availability alter microRNA (miRNA) expression. Here we address the first question by characterizing DGCR8 mutants with various degrees of deficiency in heme-binding. We observed a strikingly simple correlation between Fe(III) heme affinity in vitro and the Microprocessor activity in HeLa cells, with the heme affinity threshold for activation estimated to be between 0.6-5 pM under typical cell culture conditions. The threshold is strongly influenced by cellular heme synthesis and uptake. We suggest that the threshold reflects a labile Fe(III) heme pool in cells. Based on our understanding of DGCR8 mutants, we reanalyzed recently reported miRNA sequencing data and conclude that heme is generally required for processing canonical pri-miRNAs, that heme modulates the specificity of Microprocessor, and that cellular heme level and differential DGCR8 heme occupancy alter the expression of distinct groups of miRNAs in a hierarchical fashion. Overall, our study provides the first glimpse of a labile Fe(III) heme pool important for a fundamental physiological function and reveal principles governing how Fe(III) heme modulates miRNA maturation at a genomic scale. We also discuss potential states and biological significance of the labile Fe(III) heme pool.

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