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The development of genetic sex determination and cytologically distinct sex chromosomes leads to the potential problem of gene dosage imbalances between autosomes and sex chromosomes and also between males and females. To circumvent these imbalances, mammals have developed an elaborate system of dosage compensation that includes both upregulation a...
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Context 1
... October 2008 11:16 in the recruitment of multiple repressive chro- matin marks including histone modifications and histone variants ( Table 1; see below) (see Reference 238 for a review). As a consequence, the sex chromosomes form a distinct struc- ture called the XY body or sex body, which is heterochromatic and transcriptionally silent (66,155,240). ...
Context 2
... addition, the elucidation of Xi-and Xa- specific histone modifications, histone variants, and DNA-methylation marks added to our un- derstanding of X-inactivation as a classic epi- genetic phenomenon. Only very recently are autosomal trans-acting protein factors also be- ing characterized for their roles in various as- pects of X-inactivation ( Table 1). Nuclear com- partmentalization, X chromosome pairing, in- volvement of chromatin regulation, or small RNAs and Xa upregulation are only a few of the novel features of mammalian dosage com- pensation that have unfolded over the past few years and are pointing at new avenues of in- vestigation. ...
Similar publications
As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X i...
In female mammals, X chromosome inactivation (XCI) is a key process in the control of gene dosage compensation between X-linked genes and autosomes. Xist and Tsix , two overlapping antisense transcribed noncoding genes, are central elements of the X inactivation center ( Xic ) regulating XCI. Xist up-regulation results in coating of the entire X ch...
Susumu Ohno proposed in 1967 that, during the origin of mammalian sex chromosomes from a pair of autosomes, per-allele expression levels of X-linked genes were doubled to compensate for the degeneration of their Y homologs. This conjecture forms the foundation of the current evolutionary model of sex chromosome dosage compensation, but has been tes...
In mammals, dosage compensation is achieved by doubling expression of X-linked genes in both sexes, together with X inactivation in females. Up-regulation of the active X chromosome may be controlled by DNA sequence-based and/or epigenetic mechanisms that double the X output potentially in response to autosomal factor(s). To determine whether X exp...
Citations
... The translation process is regulated through interactions between proteincoding genes and their homologous antisense transcripts, antisense ncRNA pairs with the mRNA bases to form RNA double strands that cover key cis-elements within mRNA, subsequently guiding the binding of mRNA isoforms with splicing regulatory proteins for alternative splicing [9]. The lncRNA Xist participates in chromosome dosage compensation by regulating X chromosome inactivation [10], forms RNA double-strands with the antisense transcript Tsix through annealing, and subsequently generate small interfering RNAs upon Dicer processing, thereby participating in repressive chromatin modifications [11]. ...
... The epigenetic regulation includes DNA methylation, posttranslational histone protein modifications such as acetylation, methylation, and phosphorylation, and microRNAs (noncoding RNA) that can inhibit translation or degrade mRNAs by modulating gene expression (Dehan et al., 2009). Epigenetic control plays a crucial role during early embryonic development, such as X-inactivation in females, genomic imprinting, development, and differentiation like the formation of long-term memory and behavior (Payer and Lee, 2008;Lubin et al., 2011). In addition to this, research studies suggest that epigenetic DNA modifications on uniparental disomy also serves as an underlying mechanism for developmental disorders, neurological diseases and tumorigenesis (Zoghbi and Beaudet, 2016;Tuna et al., 2009). ...
For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.
... However, it is noteworthy that not all CGIs remain unmethylated. CGIs are methylated in certain cases where gene methylation is indispensable, such as xchromosomal inactivation and genetic imprinting [19,20]. Similarly, in particular cancer tissues, CGIs are hypermethylated, leading to the transcriptional suppression of certain tumor suppressor genes [21]. ...
... Males and females have different numbers of X-chromosomes, which could result in an imbalance in the dose of gene products associated with X during embryonic development. As a way to resolve this problem, one of the two X-chromosomes is transcriptionally silenced in female mammals through X-inactivation (Lyon 1961;Payer and Lee 2008;Wutz 2011). Furthermore, X-inactivation allows humans to tolerate sex chromosomes with abnormal numbers, such as 45, XO (Turner syndrome), 47, XXY (Klinefelter syndrome), or 47, XXX (Triple X syndrome) karyotypes. ...
The prevalence and progression of cancer differ in males and females, and thus, sexual dimorphism in tumor development directly impacts clinical research and medicine. Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in gene expression and various cellular processes, including cancer development and progression. In recent years, lncRNAs have been implicated in the differences observed in cancer incidence, progression, and treatment responses between men and women. Here, we present a brief overview of the current knowledge regarding the role of lncRNAs in cancer sex dimorphism, focusing on how they affect epigenetic processes in male and female mammalian cells. We discuss the potential mechanisms by which lncRNAs may contribute to sex differences in cancer, including transcriptional control of sex chromosomes, hormonal signaling pathways, and immune responses. We also propose strategies for studying lncRNA functions in cancer sex dimorphism. Furthermore, we emphasize the importance of considering sex as a biological variable in cancer research and the need to investigate the role lncRNAs play in mediating these sex differences. In summary, we highlight the emerging link between lncRNAs and cancer sex dimorphism and their potential as therapeutic targets.
... Most of CGIs colocalize with promoters [9] and are protected from methylation, creating transcriptionally permissive chromatin [10]. However, there are well-known examples of CGIs that become methylated during development, in a tissue-specific manner, leading to stable silencing of the associated promoters [11][12][13]. ...
Background
Inherited defects in the base-excision repair gene MBD4 predispose individuals to adenomatous polyposis and colorectal cancer, which is characterized by an accumulation of C > T transitions resulting from spontaneous deamination of 5’-methylcytosine.
Methods
Here, we have investigated the potential role of MBD4 in regulating DNA methylation levels using genome-wide transcriptome and methylome analyses. Additionally, we have elucidated its function through a series of in vitro experiments.
Results
Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair. Transcriptome and methylome analyses reveal a genome-wide hypomethylation of promoters, gene bodies and repetitive elements in the absence of MBD4 in vivo. Methylation mark loss is accompanied by a broad transcriptional derepression phenotype affecting promoters and retroelements with low methylated CpG density. MBD4 in vivo forms a complex with the mismatch repair proteins (MMR), which exhibits high bi-functional glycosylase/AP-lyase endonuclease specific activity towards methylated DNA substrates containing a G/T mismatch. Experiments using recombinant proteins reveal that the association of MBD4 with the MMR protein MLH1 is required for this activity.
Conclusions
Our data identify MBD4 as an enzyme specifically designed to repair deaminated 5-methylcytosines and underscores its critical role in safeguarding against methylation damage. Furthermore, it illustrates how MBD4 functions in normal and pathological conditions.
... Dişi memelilerde her iki X kromozomu da zigotun erken evrelerinde aktif durumdadır. Embriyonik gelişimin ileri basamaklarında X kromozomlarından bir tanesi susturulmaktadır 20 . Bir hücrede maternal X kromozomu inaktive olurken, başka bir hücrede paternal X kromozomu inaktive edilebilmektedir. ...
X kromozomunun inaktivasyonu dişi memelilerde iki tane olan X kromozomlarından bir tanesinin inaktive edilmesidir. İnaktivasyona uğrayacak X kromozomu, heterokromatin şeklinde paketlenmektedir. Böylece bu X kromozomunun üzerindeki genlerin eksprese edilmeleri önlenmektedir. İnaktivasyon işlemi, bir adet X kromozomu bulunan erkekler ile iki adet X kromozomu bulunan dişiler arasındaki dengeyi sağlamaktadır. X kromozomu inaktivasyonu, inaktive edilecek tüm X kromozomunda gerçekleştiği düşünülse de, X kromozomunun üzerindeki genlerin tamamı inaktivasyona maruz kalmayıp bir kısmı inaktivasyondan kaçmaktadır. İnsanlarda X kromozomundan kodlanan genlerin yaklaşık %12 ile 20'si kadarı inaktivasyon işleminden kaçarak eksprese olabilmektedir. Derlemede, X inaktivasyonunun mekanizmaları ele alınarak, aktivasyon sürecini ve aktivasyondan kaçan genleri inceleyeceğiz.
... Cis-acting lncRNAs regulate gene expression on the same chromosome from which they are transcribed, whereas trans-acting lncRNAs regulate gene transcription on different chromosomes. Some extensively studied cis-acting lncRNAs in vertebrates include XIST [12][13][14], RSX [15], and ROX2 [16], which regulate the expression levels of entire X chromosomes in placental mammals, marsupials, and the fruit fly, respectively. Other characterized lncRNAs can regulate genetic imprinting [17], recruit protein complexes that modify chromatin [18], or influence the expression of remote genes [19]. ...
Background
Long non-coding RNAs (lncRNAs) are defined as transcribed molecules longer than 200 nucleotides with little to no protein-coding potential. LncRNAs can regulate gene expression of nearby genes (cis-acting) or genes located on other chromosomes (trans-acting). Several methodologies have been developed to capture lncRNAs associated with chromatin at a genome-wide level. Analysis of RNA-DNA contacts can be combined with epigenetic and RNA-seq data to define potential lncRNAs involved in the regulation of gene expression.
Results
We performed Chromatin Associated RNA sequencing (ChAR-seq) in Anolis carolinensis to obtain the genome-wide map of the associations that RNA molecules have with chromatin. We analyzed the frequency of DNA contacts for different classes of RNAs and were able to define cis- and trans-acting lncRNAs. We integrated the ChAR-seq map of RNA-DNA contacts with epigenetic data for the acetylation of lysine 16 on histone H4 (H4K16ac), a mark connected to actively transcribed chromatin in lizards. We successfully identified three trans-acting lncRNAs significantly associated with the H4K16ac signal, which are likely involved in the regulation of gene expression in A. carolinensis.
Conclusions
We show that the ChAR-seq method is a powerful tool to explore the RNA-DNA map of interactions. Moreover, in combination with epigenetic data, ChAR-seq can be applied in non-model species to establish potential roles for predicted lncRNAs that lack functional annotations.
... Dosage compensation effects can overcome this problem, which is what happens in triple X syndrome (47,XXX). This is achieved by silencing the supernumerary X chromosomes by the dosage compensation mechanism of X chromosome inactivation [84]. Although in some species some autosomal dosage compensation similarly occurs [85], this has not been shown to naturally happen in mammalian systems so far. ...
Human pluripotent stem cells (PSCs), which include both embryonic and induced pluripotent stem cells, are widely used in fundamental and applied biomedical research. They have been instrumental for better understanding development and cell differentiation processes, disease origin and progression and can aid in the discovery of new drugs. PSCs also hold great potential in regenerative medicine to treat or diminish the effects of certain debilitating diseases, such as degenerative disorders. However, some concerns have recently been raised over their safety for use in regenerative medicine. One of the major concerns is the fact that PSCs are prone to errors in passing the correct number of chromosomes to daughter cells, resulting in aneuploid cells. Aneuploidy, characterised by an imbalance in chromosome number, elicits the upregulation of different stress pathways that are deleterious to cell homeostasis, impair proper embryo development and potentiate cancer development. In this review, we will summarize known molecular mechanisms recently revealed to impair mitotic fidelity in human PSCs and the consequences of the decreased mitotic fidelity of these cells. We will finish with speculative views on how the physiological characteristics of PSCs can affect the mitotic machinery and how their suboptimal mitotic fidelity may be circumvented.
... Dosage compensation effects can overcome this problem, as what happens in triple X syndrome (47,XXX). This is achieved by silencing the supernumerary X chromosomes by the dosage compensation mechanism of X chromosome inactivation [80]. Although in some species some autosomal dosage compensation similarly occurs [81], this has not been shown to naturally happen in mammalian systems so far. ...
Human pluripotent stem cells (PSCs), which include both embryonic and induced pluripotent stem cells, are widely used in fundamental and applied biomedical research. They have been instrumental for better understanding development and cell differentiation processes, disease origin and progression, and can aid in the discovery of new drugs. PSCs also hold great potential in regenerative medicine to treat or diminish the effects of certain debilitating diseases, such as degenerative disorders. However, some concerns have recently been raised over their safety for the use in regenerative medicine. One of the major concerns is the fact that PSCs are prone to errors in passing the correct number of chromosomes to daughter cells, resulting in aneuploid cells. Aneuploidy, characterised by an imbalance in chromosome number, elicits the upregulation of different stress pathways that are deleterious to cell homeostasis, impair proper embryo development and can potentiate cancer development. In this review we will summarise known molecular mechanisms recently revealed to impair mitotic fidelity in human PSCs and the consequences of the decreased mitotic fidelity of these cells. We will finish with speculative views on how the physiological characteristics of PSCs can affect the mitotic machinery and how their suboptimal mitotic fidelity may be circumvented.
... In this way, the expression of X-linked genes becomes equivalent between the two sexes, and at the same time, maintains the dosage balance between X-linked and autosomal genes [8]. This two-step model is established as a foundation of our understanding of the evolution of mammal sex chromosomes [9,10]. ...
X chromosome dosage compensation (XDC) refers to the process by which X-linked genes acquire expression equivalence between two sexes. Ohno proposed that XDC is achieved by two-fold upregulations of X-linked genes in both sexes and by silencing one X chromosome (X chromosome inactivation, XCI) in females. However, genes subject to two-fold upregulations as well as the underlying mechanism remain unclear. It’s reported that gene dosage changes may only affect X-linked dosage-sensitive genes, such as protein complex coding genes (PCGs). Our results showed that in human PCGs are more likely to escape XCI and escaping PCGs (EsP) show two-fold higher expression than inactivated PCGs (InP) or other X-linked genes at RNA and protein levels in both sexes, which suggest that EsP may achieve upregulations and XDC. The higher expressions of EsP possibly result from the upregulations of the single active X chromosome (Xa), rather than escaping expressions from the inactive X chromosome (Xi). EsP genes have relatively high expression levels in humans and lower dN/dS ratios, suggesting that they are likely under stronger selection pressure over evolutionary time. Our study also suggests that SP1 transcription factor is significantly enriched in EsP and may be involved in the up-regulations of EsP on the active X. Finally, human EsP genes in this study are enriched in the toll-like receptor pathway, NF-kB pathway, apoptotic pathway, and abnormal mental, developmental and reproductive phenotypes. These findings suggest misregulations of EsP may be involved in autoimmune, reproductive, and neurological diseases, providing insight for the diagnosis and treatment of these diseases.
