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 Cutting Edge: CXCR3 Escapes X Chromosome Inactivation in T Cells during Infection: Potential Implications for Sex Differences in Immune Responses

2019 ◽  
Vol 203 (4) ◽  
pp. 789-794 ◽  
Author(s):  
Steve Oghumu ◽  
Sanjay Varikuti ◽  
James C. Stock ◽  
Greta Volpedo ◽  
Noushin Saljoughian ◽  
...  
Keyword(s):  
T Cells ◽  
Sex Differences ◽  
Immune Responses ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Cutting Edge ◽  
Chromosome Inactivation

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.

scholarly journals X-chromosome dosage as a modulator of pluripotency, signalling and differentiation?

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160366 ◽  
Author(s):  
Edda G. Schulz
Keyword(s):  
Stem Cells ◽  
Sex Differences ◽  
Embryonic Stem Cells ◽  
X Chromosome ◽  
Mammalian Species ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Hormone Production ◽  
Similar Phenotype

Already during early embryogenesis, before sex-specific hormone production is initiated, sex differences in embryonic development have been observed in several mammalian species. Typically, female embryos develop more slowly than their male siblings. A similar phenotype has recently been described in differentiating murine embryonic stem cells, where a double dose of the X-chromosome halts differentiation until dosage-compensation has been achieved through X-chromosome inactivation. On the molecular level, several processes associated with early differentiation of embryonic stem cells have been found to be affected by X-chromosome dosage, such as the transcriptional state of the pluripotency network, the activity pattern of several signal transduction pathways and global levels of DNA-methylation. This review provides an overview of the sex differences described in embryonic stem cells from mice and discusses a series of X-linked genes that are associated with pluripotency, signalling and differentiation and their potential involvement in mediating the observed X-dosage–dependent effects. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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 Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

Cell Reports ◽  
2020 ◽  
Vol 33 (10) ◽  
pp. 108485
Author(s):  
Sven Hendrik Hagen ◽  
Florian Henseling ◽  
Jana Hennesen ◽  
Hélène Savel ◽  
Solenne Delahaye ◽  
...  
Keyword(s):  
Sex Differences ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Type I ◽  
Type I Ifn

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.

95 DOSAGE COMPENSATION OF X CHROMOSOME INACTIVATION CENTER (XIC)-LINKED GENES IS ALREADY ACHIEVED IN PORCINE BLASTOCYST

2015 ◽  
Vol 27 (1) ◽  
pp. 140
Author(s):  
J. Y. Hwang ◽  
J.-N. Oh ◽  
D.-K. Lee ◽  
C.-H. Park ◽  
C.-K. Lee
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Cell Biology ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Linked Gene ◽  
Male And Female ◽  
Expression Levels ◽  
Species Specific

X-chromosome inactivation (XCI) is an epigenetically essential process for balancing dosage of X-linked genes between male and female eutherian. Importance of this complex and species-specific event has been highlighted recently in developmental and stem cell biology. However, the process has been confirmed only in restricted species, even though the species-specific studies are needed for comprehensive understanding of XCI in specific species. XCI is regulated by the various genes, many of which are coded on the X chromosome inactivation centre (XIC). Among the XIC-linked genes, especially non-coding RNA (ncRNA) like XIST, which is master gene for XCI, are known to regulate XIC. But the centre is not identified in various species. In this study, we identified XIC in pig and analysed the dosage differences of XIC-linked gene in porcine embryos. At first, the centre was searched in pig. The genomic length of the porcine XIC was similar to human XIC and the order and coding strand of the counterparts in pig XIC were same as the human XIC-linked genes. However, sequence comparison between human XIC-linked gene and its porcine counterpart showed that ncRNA around XIST were less conserved rather than protein-coding genes. This would be caused by rapid evolution of genomic region harboring ncRNA. The expression of XIC-linked genes was compared between male and female porcine embryonic fibroblast (PEF) to confirm that dosage compensation is completed in PEF. Most of the genes were not expressed sex-specifically, but two genes, XIST and an uncharacterized gene, LOC102165544, were expressed female preferentially in PEF. Interestingly, LOC102165544, which had low sequence homology with human JPX, was expressed about 2-fold higher in female PEF. This means that XIST and LOC102165544 are XCI-escaping genes. Among the XIC-linked genes, CHIC1, XIST, LOC102165544, and RLIM were stably expressed in embryonic stage, and XIST and LOC102165544 were up-regulated after morula formation. As XIST accumulation is a requisite for XCI initiation, expression levels of the 4 genes between male and female blastocysts were compared. Interestingly, expression levels of CHIC1 and RLIM were not different in male and female blastocysts. This means their dosage would be already compensated in porcine blastocyst. Additionally, to confirm loci of the 2 genes CHIC1 and RLIM harbor one of the inactive alleles in female blastocyst, the DNA methylation pattern was examined. One of the CHIC1 alleles was inactive but RLIM CpG site was hypo-methylated in female blastocyst. This would indicate that one of the RLIM alleles is transcriptionally inactivated by chromatin modification rather than by DNA methylation of the allele. Regulatory regions of XIST and LOC102165544 were demethylated in blastocyst and this showed XCI was not finished in porcine blastocyst. Conclusively, our results demonstrate the XCI already occurs in porcine blastocyst at least one gene but it is not completed.This work was supported by Next BioGreen21 program (PJ009493), Rural Development Administration, Republic of Korea.

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