scholarly journals A symmetric toggle switch explains the onset of random X inactivation in different mammals

2017 ◽  
Author(s):  
Verena Mutzel ◽  
Ikuhiro Okamoto ◽  
Ilona Dunkel ◽  
Mitinori Saitou ◽  
Luca Giorgetti ◽  
...  
Keyword(s):  
X Chromosome ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Toggle Switch ◽  
Model Predictions ◽  
Gene Regulatory ◽  
Stable Mono

SummaryGene-regulatory networks control establishment and maintenance of alternative gene expression states during development. A particular challenge is the acquisition of opposing states by two copies of the same gene, as it is the case in mammals for Xist at the onset of random X-chromosome inactivation (XCI). The regulatory principles that lead to stable mono-allelic expression of Xist remain unknown. Here, we uncovered the minimal Xist regulatory network, by combining mathematical modeling and experimental validation of central model predictions. We identified a symmetric toggle switch as the basis for random mono-allelic Xist up-regulation, which reproduces data from several mutant, aneuploid and polyploid murine cell lines with various Xist expression patterns. Moreover, this toggle switch explains the diversity of strategies employed by different species at the onset of XCI. In addition to providing a unifying conceptual framework to explore X-chromosome inactivation across mammals, our study sets the stage for identifying the molecular mechanisms required to initiate random XCI.

scholarly journals X-Chromosome Inactivation and Autosomal Random Monoallelic Expression as “Faux Amis”

2021 ◽  
Vol 9 ◽  
Author(s):  
Vasco M. Barreto ◽  
Nadiya Kubasova ◽  
Clara F. Alves-Pereira ◽  
Anne-Valerie Gendrel
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Gene Expression Regulation ◽  
Phenotypic Diversity ◽  
X Chromosome Inactivation ◽  
Cellular Level ◽  
Chromosome Inactivation ◽  
Monoallelic Expression ◽  
Distinctive Features ◽  
Faux Amis

X-chromosome inactivation (XCI) and random monoallelic expression of autosomal genes (RMAE) are two paradigms of gene expression regulation where, at the single cell level, genes can be expressed from either the maternal or paternal alleles. X-chromosome inactivation takes place in female marsupial and placental mammals, while RMAE has been described in mammals and also other species. Although the outcome of both processes results in random monoallelic expression and mosaicism at the cellular level, there are many important differences. We provide here a brief sketch of the history behind the discovery of XCI and RMAE. Moreover, we review some of the distinctive features of these two phenomena, with respect to when in development they are established, their roles in dosage compensation and cellular phenotypic diversity, and the molecular mechanisms underlying their initiation and stability.

Genes that Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts

Circulation ◽  
2022 ◽  
Author(s):  
Brian A. Aguado ◽  
Cierra J. Walker ◽  
Joseph C. Grim ◽  
Megan E. Schroeder ◽  
Dilara Batan ◽  
...  
Keyword(s):  
Sex Differences ◽  
X Chromosome ◽  
Molecular Mechanisms ◽  
Smooth Muscle Actin ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Matrix Stiffness ◽  
Alpha Smooth Muscle Actin ◽  
Male And Female ◽  
Hydrogel Matrix

Background: Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored. Methods: Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-sequencing was used to define pathways involved in driving sex-dependent activation. Interventions using small molecule inhibitors and small interfering RNA (siRNA) transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. Results: In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, alpha-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Conclusions: Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.

scholarly journals Comparative analyses of saprotrophy in Salisapilia sapeloensis and diverse plant pathogenic oomycetes reveal lifestyle-specific gene expression

2020 ◽  
Vol 96 (11) ◽  
Author(s):  
Sophie de Vries ◽  
Jan de Vries ◽  
John M Archibald ◽  
Claudio H Slamovits
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Plant Pathogens ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Reference Points ◽  
Global Perspective ◽  
Specific Gene ◽  
Gene Regulatory ◽  
Specific Array

ABSTRACT Oomycetes include many devastating plant pathogens. Across oomycete diversity, plant-infecting lineages are interspersed by non-pathogenic ones. Unfortunately, our understanding of the evolution of lifestyle switches is hampered by a scarcity of data on the molecular biology of saprotrophic oomycetes, ecologically important primary colonizers of dead tissue that can serve as informative reference points for understanding the evolution of pathogens. Here, we established Salisapilia sapeloensis as a tractable system for the study of saprotrophic oomycetes. We generated multiple transcriptomes from S. sapeloensis and compared them with (i) 22 oomycete genomes and (ii) the transcriptomes of eight pathogenic oomycetes grown under 13 conditions. We obtained a global perspective on gene expression signatures of oomycete lifestyles. Our data reveal that oomycete saprotrophs and pathogens use similar molecular mechanisms for colonization but exhibit distinct expression patterns. We identify a S. sapeloensis-specific array and expression of carbohydrate-active enzymes and putative regulatory differences, highlighted by distinct expression levels of transcription factors. Salisapilia sapeloensis expresses only a small repertoire of candidates for virulence-associated genes. Our analyses suggest lifestyle-specific gene regulatory signatures and that, in addition to variation in gene content, shifts in gene regulatory networks underpin the evolution of oomycete lifestyles.

STATISTICAL MECHANICS MODELS FOR X-CHROMOSOME INACTIVATION

2010 ◽  
Vol 13 (03) ◽  
pp. 367-376
Author(s):  
ANTONIO SCIALDONE ◽  
MARIO NICODEMI
Keyword(s):  
Statistical Mechanics ◽  
X Chromosome ◽  
Molecular Mechanisms ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Regulatory Mechanisms ◽  
Random Choice ◽  
X Chromosomes ◽  
Cellular Processes ◽  
Regulatory Processes

We present statistical mechanics models to understand the physical and molecular mechanisms of X-Chromosome Inactivation (XCI), the process whereby a female mammal cell inactivates one of its two X-chromosomes. During XCI, X-chromosomes undergo a series of complex regulatory processes. At the beginning of XCI, the X's recognize and pair, then only one X which is randomly chosen is inactivated. Afterwards, the two X's move to different positions in the cell nucleus according to their different status (active/silenced). Our models illustrate about the still mysterious physical bases underlying all these regulatory steps, i.e., X-chromosome pairing, random choice of inactive X, and "shuttling" of the X's to their post-XCI locations. Our models are based on general and robust thermodynamic roots, and their validity can go beyond XCI, to explain analogous regulatory mechanisms in a variety of cellular processes.

X-chromosome inactivation: molecular mechanisms from the human perspective

2011 ◽  
Vol 130 (2) ◽  
pp. 175-185 ◽  
Author(s):  
Christine Yang ◽  
Andrew G. Chapman ◽  
Angela D. Kelsey ◽  
Jakub Minks ◽  
Allison M. Cotton ◽  
...  
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

scholarly journals The tandem repeat modules of Xist lncRNA: a swiss army knife for the control of X-chromosome inactivation

2021 ◽  
Author(s):  
Ana Cláudia Raposo ◽  
Miguel Casanova ◽  
Anne-Valerie Gendrel ◽  
Simão Teixeira da Rocha
Keyword(s):  
X Chromosome ◽  
Tandem Repeat ◽  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Modular Organization ◽  
Functional Specialization

X-inactive-specific transcript (Xist) is a long non-coding RNA (lncRNA) essential for X-chromosome inactivation (XCI) in female placental mammals. Thirty years after its discovery, it is still puzzling how this lncRNA triggers major structural and transcriptional changes leading to the stable silencing of an entire chromosome. Recently, a series of studies in mouse cells have uncovered domains of functional specialization within Xist mapping to conserved tandem repeat regions, known as Repeats A-to-F. These functional domains interact with various RNA binding proteins (RBPs) and fold into distinct RNA structures to execute specific tasks in a synergistic and coordinated manner during the inactivation process. This modular organization of Xist is mostly conserved in humans, but recent data point towards differences regarding functional specialization of the tandem repeats between the two species. In this review, we summarize the recent progress on understanding the role of Xist repetitive blocks and their involvement in the molecular mechanisms underlying XCI. We also discuss these findings in the light of the similarities and differences between mouse and human Xist.

scholarly journals Comparative analyses of saprotrophy in Salisapilia sapeloensis and diverse plant pathogenic oomycetes reveal lifestyle-specific gene expression

2019 ◽  
Author(s):  
Sophie de Vries ◽  
Jan de Vries ◽  
John M Archibald ◽  
Claudio H Slamovits
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Plant Pathogens ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Reference Points ◽  
Global Perspective ◽  
Specific Gene ◽  
Gene Regulatory ◽  
Specific Array

Oomycetes include many well-studied, devastating plant pathogens. Across oomycete diversity, plant-infecting lineages are interspersed by non-pathogenic ones. Unfortunately, our understanding of the evolution of lifestyle switches is hampered by a scarcity of data on the molecular biology of saprotrophic oomycetes, ecologically important primary colonizers of dead tissue that can serve as informative reference points for understanding the evolution of pathogens. Here, we established Salisapilia sapeloensis growing on axenic litter as a tractable system for the study of saprotrophic oomycetes. We generated multiple transcriptomes from S. sapeloensis and compared them to (a) 22 oomycete genomes and (b) the transcriptomes of eight pathogenic oomycetes grown under 13 conditions (three pathogenic lifestyles, six hosts/substrates, and four tissues). From these analyses we obtained a global perspective on the gene expression signatures of oomycete lifestyles. Our data reveal that oomycete saprotrophs and pathogens use generally similar molecular mechanisms for colonization, but exhibit distinct expression patterns. We identify S. sapeloensis' specific array and expression of carbohydrate-active enzymes and regulatory differences in pathogenicity-associated factors, including the virulence factor EpiC2B. Further, S. sapeloensis was found to express only a small repertoire of effector genes. In conclusion, our analyses reveal lifestyle-specific gene regulatory signatures and suggest that, in addition to variation in gene content, shifts in gene regulatory networks might underpin the evolution of oomycete lifestyles.

scholarly journals The lncRNAs at X Chromosome Inactivation Center: Not Just a Matter of Sex Dosage Compensation

2022 ◽  
Vol 23 (2) ◽  
pp. 611
Author(s):  
Chiara Siniscalchi ◽  
Armando Di Palo ◽  
Aniello Russo ◽  
Nicoletta Potenza
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Regulatory Networks ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Linked Gene ◽  
Regulatory Circuit ◽  
Rna Targets ◽  
Inactivation Center

Non-coding RNAs (ncRNAs) constitute the majority of the transcriptome, as the result of pervasive transcription of the mammalian genome. Different RNA species, such as lncRNAs, miRNAs, circRNA, mRNAs, engage in regulatory networks based on their reciprocal interactions, often in a competitive manner, in a way denominated “competing endogenous RNA (ceRNA) networks” (“ceRNET”): miRNAs and other ncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs, titrating their availability and thus competing with the binding to other RNA targets. The unbalancing of any network component can derail the entire regulatory circuit acting as a driving force for human diseases, thus assigning “new” functions to “old” molecules. This is the case of XIST, the lncRNA characterized in the early 1990s and well known as the essential molecule for X chromosome inactivation in mammalian females, thus preventing an imbalance of X-linked gene expression between females and males. Currently, literature concerning XIST biology is becoming dominated by miRNA associations and they are also gaining prominence for other lncRNAs produced by the X-inactivation center. This review discusses the available literature to explore possible novel functions related to ceRNA activity of lncRNAs produced by the X-inactivation center, beyond their role in dosage compensation, with prospective implications for emerging gender-biased functions and pathological mechanisms.

Preferential X-chromosome inactivation, DNA methylation and imprinting

Development ◽  
1990 ◽  
Vol 108 (Supplement) ◽  
pp. 55-62
Author(s):  
Marilyn Monk ◽  
Mark Grant
Keyword(s):  
Dna Methylation ◽  
Early Development ◽  
X Chromosome ◽  
Expression Patterns ◽  
Genetic Material ◽  
X Chromosome Inactivation ◽  
Differential Methylation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Embryonic Tissues

Non-random X-chromosome inactivation in mammals was one of the first observed examples of differential expression dependent on the gamete of origin of the genetic material. The paternally-inherited X chromosome is preferentially inactive in all cells of female marsupials and in the extra-embryonic tissues of developing female rodents. Some form of parental imprinting during male and female gametogenesis must provide a recognition signal that determines the nonrandomness of X-inactivation but its nature is thus far unknown. In the mouse, the imprint distinguishing the X chromosomes in the extra-embryonic tissues must be erased early in development since X-inactivation is random in the embryonic cells. Random X-chromosome inactivation leads to cellular mosaicism in expression and differential methylation of active and inactive X-linked genes. Transgene imprinting shares many features with X-inactivation, including differential DNA methylation. In this paper we consider when methylation differences in early development affecting X-chromosome activity and imprinting are established. There are processes of methylation and demethylation occurring in early development, as well as changes in the activity of the DNA methylase itself. Methylation of a specific CpG site associated with activity of the X-linked PGK-1 gene has been studied. This site is already methylated on the inactive X chromosome by 6.5 days' gestation, close to the time of X-inactivation. However, differential methylation of this site is not the primary imprint marking the paternal X chromosome for preferential inactivation in the extra-embryonic membranes. A consideration of factors influencing both X-chromosome inactivation and imprinting suggests that a process of communication and comparison between nonidentical alleles might by the basis for the differential modification and expression patterns observed.

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