X inactivation is the process that brings about the dosage equivalence of X‐linked genes in females to that of males. This complex process initiated at a very early stage of female embryonic development is orchestrated by long non‐coding RNAs transcribed in both sense and antisense orientation. Recent studies present contradicting evidence for the role of small RNAs and RNase III enzyme Dicer in the X inactivation process. In this review, I discuss these results in the overall perspective of (...) X inactivation and gene silencing. (shrink)

The spatial organization of genomes is becoming increasingly understood. In mammals, where it is most investigated, this organization ties in with transcription, so an important research objective is to understand whether gene activity is a cause or a consequence of genome folding in space. In this regard, the phenomena of X‐chromosome inactivation and reactivation open a unique window of investigation because of the singularities of the inactive X chromosome. Here we focus on the cause–consequence nexus between genome conformation and (...) transcription and explain how recent results about the structural changes associated with inactivation and reactivation of the X chromosome shed light on this problem. (shrink)

X chromosome inactivation is the mammalian answer to the dilemma of dosage compensation between males and females. The study of this fascinating form of chromosome-wide gene regulation has yielded surprising insights into early development and cellular memory. In the past few months, three papers1-3 reported unexpected findings about the paternal X chromosome (Xp). All three studies agree that the Xp is imprinted to become inactive earlier than ever suspected during embryonic development. Although apparently incomplete, this early form of (...) class='Hi'>inactivation insures dosage compensation throughout development. Silencing of the Xp persists in cells of extraembryonic tissues, but it is erased and followed by random X inactivation in cells of the embryo proper. These findings challenge several aspects of the current view of X inactivation during early development and may have profound impact on studies of pluripotency and epigenetics. BioEssays 26:821–824, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

X chromosome inactivation (XCI) is an essential epigenetic process that ensures X‐linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a (...) uniform mechanism in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi. (shrink)

X‐chromosome inactivation refers to the coordinate regulation of almost all genes on the mammalian × chromosome. Most models for × chromosome inactivation suppose a role for methylation of × chromosome DNA sequences and/or the heterochromatinization of large «domains» of the × chromosome containing many genes.1 Some recent work concerning the expression of X‐linked transgenes, and parallels between regulated expression of sex‐linked genes in invertebrates and mammals, suggest that × chromosome inactivation may be a gene‐by‐gene event mediated by (...) the interaction between regulatory sequences common to all X‐linked genes and soluble activators and repressors. (shrink)

Mammals have a very complex, tightly controlled, and developmentally regulated process of dosage compensation. One form of the process equalizes expression of the X‐linked genes, present as a single copy in males (XY) and as two copies in females (XX), by inactivation of one of the two X‐chromosomes in females. The second form of the process leads to balanced expression between the X‐linked and autosomal genes by transcriptional upregulation of the active X in males and females. However, not all (...) X‐linked genes are absolutely balanced. This review is focused on the recent advances in studying the dosage compensation phenomenon in mammals. (shrink)

X‐chromosome inactivation ensures dosage compensation between the sexes in mammals by randomly choosing one out of the two X chromosomes in females for inactivation. This process imposes a plethora of questions: How do cells count their X chromosome number and ensure that exactly one stays active? How do they randomly choose one of two identical X chromosomes for inactivation? And how do they stably maintain this state of monoallelic expression? Here, different regulatory concepts and their plausibility are (...) evaluated in the context of theoretical studies that have investigated threshold behavior, ultrasensitivity, and bistability through mathematical modeling. It is discussed how a twofold difference between a single and a double dose of X‐linked genes might be converted to an all‐or‐nothing response and how mutually exclusive expression can be initiated and maintained. Finally, candidate factors that might mediate the proposed regulatory principles are reviewed. (shrink)

In humans over 15% of X‐linked genes have been shown to ‘escape’ from X‐chromosome inactivation (XCI): they continue to be expressed to some extent from the inactive X chromosome. Mono‐allelic expression is anticipated within a cell for genes subject to XCI, but random XCI usually results in expression of both alleles in a cell population. Using a study of allelic expression from cultured lymphoblasts and fibroblasts, many of which showed substantial skewing of XCI, we recently reported that the expression (...) of genes lies on a contiunuum between those that are subject to inactivation, and those that escape. We now review allelic expression studies from mouse, and discuss the variability in escape seen in both humans and mice in genic expression levels, between X chromosomes and between tissues. We also discuss current knowledge of the heterochromatic features, DNA elements and three‐dimensional topology of the inactive X that contribute to the balance of expression from the otherwise inactive X chromosome. (shrink)

X chromosome centromeric drive may explain the prevalence of polycystic ovary syndrome and contribute to oocyte aneuploidy, menopause, and other conditions. The mammalian X chromosome may be vulnerable to meiotic drive because of X inactivation in the female germline. The human X pericentromeric region contains genes potentially involved in meiotic mechanisms, including multiple SPIN1 and ZXDC paralogs. This is consistent with a multigenic drive system comprising differential modification of the active and inactive X chromosome centromeres in female primordial germ (...) cells and preferential segregation of the previously inactivated X chromosome centromere to the polar body at meiosis I. The drive mechanism may explain differences in X chromosome regulation in the female germlines of the human and mouse and, based on the functions encoded by the genes in the region, the transmission of X pericentromeric genetic or epigenetic variants to progeny could contribute to preeclampsia, autism, and differences in sexual differentiation. (shrink)

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special (...) challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. (shrink)

In mice, dosage compensation of X‐linked gene expression is achieved through the inactivation of one of the two X‐chromosomes in XX female cells. The complex epigenetic process leading to X‐inactivation is largely controlled by Xist and Tsix, two non‐coding genes of opposing function. Xist RNA triggers X‐inactivation by coating the inactive X, while Tsix is critical for the designation of the active X‐chromosome through cis‐repression of Xist RNA accumulation. Recently, a plethora of trans‐acting factors and cis‐regulating elements (...) have been suggested to act as key regulators of either Xist, Tsix or both; these include ubiquitous factors such as Yy1 and Ctcf, developmental proteins such as Nanog, Oct4 and Sox2, and X‐linked regulators such as Rnf12. In this paper we summarise recent advances in our knowledge of the regulation of Xist and Tsix in embryonic stem (ES) and differentiating ES cells. (shrink)

The creeping vole Microtus oregoni exhibits remarkably transformed sex chromosome biology, with complete chromosome drive/drag, X‐Y fusions, sex reversed X complements, biased X inactivation, and X chromosome degradation. Beginning with a selfish X chromosome, I propose a series of adaptations leading to this system, each compensating for deleterious consequences of the preceding adaptation: (1) YY embryonic inviability favored evolution of a selfish feminizing X chromosome; (2) the consequent Y chromosome transmission disadvantage favored X‐Y fusion (“XP”); (3) Xist‐based silencing of (...) Y‐derived XP genes favored a second X‐Y fusion (“XM”); (4) X chromosome dosage‐related costs in XPXM males favored the evolution of XM loss during spermatogenesis; (5) X chromosomal dosage‐related costs in XM0 females favored the evolution of XM drive during oogenesis; and (6) degradation of the non‐recombining XP favored the evolution of biased X chromosome inactivation. I discuss recurrent rodent sex chromosome transformation, and selfish genes as a constructive force in evolution. (shrink)

In this paper, we hypothesize that X chromosome-associated mechanisms, which affect X-linked genes and are behind the immunological advantage of females, may also affect X-linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome-located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human and mouse X (...) chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X-linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular epidemiology and (...) resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine. (shrink)

Recent approaches towards an understanding of the molecular basis of X‐chromosome inactivation in mammals suggest that regulation is due to multiple events including DNA methylation.

Recent studies based on next‐generation DNA sequencing have revealed that the female inactive X chromosome is replicated in a rapid, unorganized manner, and undergoes increased rates of mutation. These observations link the organization of DNA replication timing to gene regulation on one hand, and to the generation of mutations on the other hand. More generally, the exceptional biology of the inactive X chromosome highlights general principles of genome replication. Cells may control replication timing by a combination of intrinsic replication origin (...) properties, local chromatin states and global levels of replication factors, leading to a functional separation between the activity of genes and their mutation. (shrink)

Monoallelic gene expression has played a significant role in the evolution of mammals enabling the expansion of a vast repertoire of olfactory receptor types and providing increased sensitivity and diversity. Monoallelic expression of immune receptor genes has also increased diversity for antigen recognition, while the same mechanism that marks a single allele for preferential rearrangement also provides a distinguishing feature for directing hypermutations. Random monoallelic expression of the X chromosome is necessary to balance gene dosage across sexes. In marsupials only (...) the maternal X chromosome is expressed, while in eutherian mammals the paternal X genes are silenced in the developing placenta and early blastocyst. These examples of epigenetic gene regulation commonly employ asynchrony of replication, the binding of polycomb proteins and antisense RNA, and histone modifications to chromatin structure. The same is true for genomic imprinting which among vertebrates is unique to mammals and represents a special kind of epigenetic modification that is heritable according to parent of origin. Genomic imprinting pervades many aspects of mammalian growth and evolution but in particular has played a significant role in the co‐adaptive evolution of the mother and foetus. (shrink)

DNA repetitions may provoke heterochromatinization. We explore here a model in which multiple cis‐acting sequences that display no silencing activity on their own (protosilencers) may cooperate to establish and maintain a heterochromatin domain efficiently. Protosilencers, first defined in budding yeast, have now been found in a wide range of genomes where they appear to stabilize and to extend the propagation of heterochromatin domains. Strikingly, isolated or moderately repeated protosilencers can also be found in promoters where they participate in transcriptional activation (...) and have insulation functions. This suggests that the proper juxtaposition of a threshold number of protosilencers converts them from neutral or transactivating elements into ones that nucleate heterochromatin. Interactions might be transient or permanent, and are likely to occur over distances by looping. This model provides a conceptual framework for as varied phenomena as telomere‐driven silencing in Drosophila, X inactivation in mammals, and rDNA silencing in S. cerevisiae. It may also account for the silencing that occurs when multiple copies of a transgene are inserted in tandem. BioEssays 24:828–835, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

In most discussions of the evolution of sex chromosomes, it is presumed that the morphological differences between the X and Y were initiated by genetic changes. An alternative possibility is that, in the early stages, a key role was played by epigenetic modifications of chromatin structure that did not depend directly on genetic changes. Such modifications could have resulted from spontaneous epimutations at a sex‐determining locus or, in mammals, from selection in females for the epigenetic silencing of imprinted regions of (...) the paternally derived sex chromosome. Other features of mammalian sex chromosomes that are easier to explain if the epigenetic dimension of chromosome evolution is considered include the relatively large number of X‐linked genes associated with human brain development, and the overrepresentation of spermatogenesis genes on the X. Both may be evolutionary consequences of dosage compensation through X‐inactivation. BioEssays 26:1327–1332, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Recent reports that human pluripotent stem cells can be captured in a spectrum of states with variable properties has prompted a re‐evaluation of how pluripotency is acquired and stabilised. The latest additions to the stem cell hierarchy open up opportunities for understanding human development, reprogramming, and cell state transitions more generally. Many of the new cell lines have been collectively termed ‘naïve’ human pluripotent stem cells to distinguish them from the conventional ‘primed’ cells. Here, several transcriptional and epigenetic hallmarks of (...) human pluripotent states in the recently described cell lines are reviewed and evaluated. Methods to derive and identify human naïve pluripotent stem cells are also discussed, with a focus on the uses and future developments of state‐specific reporter cell lines and cell‐surface proteins. Finally, opportunities and uncertainties in naïve stem cell biology are highlighted, and the current limitations of human naïve pluripotent stem cells considered, particularly in the context of differentiation. (shrink)

Mammalian sex chromosomes exhibit marked sexual dimorphism in behavior during gametogenesis. During oogenesis, the X chromosomes pair and participate in unrestricted recombination; both are transcriptionally active. However, during spermatogenesis the X and Y chromosomes experience spatial restriction of pairing and recombination, are transcriptionally inactive, and form a chromatin domain that is markedly different from that of the autosomes. Thus the male germ cell has to contend with the potential loss of X‐encoded gene products, and it appears that coping strategies have (...) evolved. Genetic control of sex‐chromosome inactivation during spermatogenesis does not involve pairing or the presence of the Y chromosome or an intact X chromosome, and may therefore be under exogenous control by the gonad. Sex‐chromosome reactivation during oogenesis and inactivation during spermatogenesis probably reflect specific meiotic events such as recombination. Understanding these phenomena may help explain other sex‐related differences in genetic recombination. (shrink)

Recent studies indicate that mammalian chromosomes contain discretecis‐acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non‐coding RNA gene ASAR6 results in late replication, an under‐condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono‐allelic expression and asynchronous replication timing. (...) Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types ofcis‐acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. (shrink)

We focus here on the intercalary heterochromatin (IH) of Drosophila melanogaster and, in particular, its molecular properties. In the polytene chromosomes of Drosophila, IH is represented by a reproducible set of dense bands scattered along the euchromatic arms. IH contains mainly unique DNA sequences, and shares certain features with other heterochromatin types such as pericentric, telomeric, and PEV‐induced heterochromatin, the inactive mammalian X‐chromosome and the heterochromatized male chromosome set in coccids. These features are transcriptional silencing, chromatin compactness, late DNA replication, (...) underrreplication or elimination in somatic cells, and formation of the heterochromatin state in early embryogenesis. Post‐translational modification of histones and the specific nonhistone protein complexes are shown to participate in the establishment and maintenance of silencing for all heterochromatin types. Many IH regions contain binding sites for HP1 and/or Pc‐G proteins and all the regions are sites of heterochromatin‐associated SuUR protein. Some IH regions are known to contain homeotic genes. Summarizing these data, we suggest that IH regions comprise stable inactivated genes, whose silencing is developmentally programmed. BioEssays 25:1040–1051, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Monitoring the environment for visual events while performing a concurrent task requires adjustment of visual processing priorities. By use of Bundesen's (1990) Theory of Visual Attention (TVA), we investigated how monitoring for an object-based brief event affected distinct components of visual attention in a concurrent task. The perceptual salience of the event was varied. Monitoring reduced the processing speed in the concurrent task, and the reduction was stronger when the event was less salient. The monitoring task neither affected the temporal (...) threshold of conscious perception nor the storage capacity of visual short-term memory nor the efficiency of top-down controlled attentional selection. (shrink)

This paper aims to explore one significant yet insufficiently elaborated aspect of valuing, namely the positional nature of valuing, which essentially reveals the fact that the valuer occupies a particular position or takes a specific viewpoint in relation to the object being valued. This positional nature of valuing does not merely embody a specific viewpoint from which the valuer’s beliefs, attitudes, reasons, and emotions are conveyed in a complex manner towards the valued object, but also constitute a particular position from (...) which the valuer engages with the valued object in a reason-giving manner. As systematically elaborated and lucidly revealed by this paper, this positional nature of valuing will on the one hand elucidate the conceptual interlock between ‘valuing’ and ‘valuable’ along the value-reason nexus with reference to arguments by T.M. Scanlon and Samuel Scheffler. On the other hand, it will also illuminate why we may have reason to value something from the perspective of practical reasoning. (shrink)