Showing papers on "Dosage compensation published in 2017"

Genetic compensation: A phenomenon in search of mechanisms.

Abstract: Several recent studies in a number of model systems including zebrafish, Arabidopsis, and mouse have revealed phenotypic differences between knockouts (i.e., mutants) and knockdowns (e.g., antisense-treated animals). These differences have been attributed to a number of reasons including off-target effects of the antisense reagents. An alternative explanation was recently proposed based on a zebrafish study reporting that genetic compensation was observed in egfl7 mutant but not knockdown animals. Dosage compensation was first reported in Drosophila in 1932, and genetic compensation in response to a gene knockout was first reported in yeast in 1969. Since then, genetic compensation has been documented many times in a number of model organisms; however, our understanding of the underlying molecular mechanisms remains limited. In this review, we revisit studies reporting genetic compensation in higher eukaryotes and outline possible molecular mechanisms, which may include both transcriptional and posttranscriptional processes.

Sex chromosome evolution: historical insights and future perspectives

Abstract: Many separate-sexed organisms have sex chromosomes controlling sex determination. Sex chromosomes often have reduced recombination, specialized (frequently sex-specific) gene content, dosage compensation and heteromorphic size. Research on sex determination and sex chromosome evolution has increased over the past decade and is today a very active field. However, some areas within the field have not received as much attention as others. We therefore believe that a historic overview of key findings and empirical discoveries will put current thinking into context and help us better understand where to go next. Here, we present a timeline of important conceptual and analytical models, as well as empirical studies that have advanced the field and changed our understanding of the evolution of sex chromosomes. Finally, we highlight gaps in our knowledge so far and propose some specific areas within the field that we recommend a greater focus on in the future, including the role of ecology in sex chromosome evolution and new multilocus models of sex chromosome divergence.

Xist -dependent imprinted X inactivation and the early developmental consequences of its failure

Abstract: The long noncoding RNA Xist is expressed from only the paternal X chromosome in mouse preimplantation female embryos and mediates transcriptional silencing of that chromosome. In females, absence of Xist leads to postimplantation lethality. Here, through single-cell RNA sequencing of early preimplantation mouse embryos, we found that the initiation of imprinted X-chromosome inactivation absolutely requires Xist. Lack of paternal Xist leads to genome-wide transcriptional misregulation in the early blastocyst and to failure to activate the extraembryonic pathway that is essential for postimplantation development. We also demonstrate that the expression dynamics of X-linked genes depends on the strain and parent of origin as well as on the location along the X chromosome, particularly at the first 'entry' sites of Xist. This study demonstrates that dosage-compensation failure has an effect as early as the blastocyst stage and reveals genetic and epigenetic contributions to orchestrating transcriptional silencing of the X chromosome during early embryogenesis.

Novel players in X inactivation: insights into Xist-mediated gene silencing and chromosome conformation.

Abstract: This Review highlights recent breakthroughs in X-chromosome inactivation and discusses how the multitasking RNA Xist can structurally and functionally transform an active chromosome into uniquely organized facultative heterochromatin.

Evolution of Sex Chromosome Dosage Compensation in Animals: A Beautiful Theory, Undermined by Facts and Bedeviled by Details

Abstract: Many animals with genetic sex determination harbor heteromorphic sex chromosomes, where the heterogametic sex has half the gene dose of the homogametic sex. This imbalance, if reflected in the abundance of transcripts or proteins, has the potential to deleteriously disrupt interactions between X-linked and autosomal loci in the heterogametic sex. Classical theory predicts that molecular mechanisms will evolve to provide dosage compensation that recovers expression levels comparable to ancestral expression prior to sex chromosome divergence. Such dosage compensating mechanisms may also, secondarily, result in balanced sex-linked gene expression between males and females. However, numerous recent studies addressing sex chromosome dosage compensation (SCDC) in a diversity of animals have yielded a surprising array of patterns concerning dosage compensation in the heterogametic sex, as well as dosage balance between sexes. These results substantially contradict longstanding theory, catalyzing both novel perspectives and new approaches in dosage compensation research. In this review, we summarize the theory, analytical approaches, and recent results concerning evolutionary patterns of SCDC in animals. We also discuss methodological challenges and discrepancies encountered in this research, which often underlie conflicting results. Finally, we discuss what outstanding questions and opportunities exist for future research on SCDC.

Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing

Abstract: In female mammals, one X chromosome is transcriptionally inactivated (XCI), leading to dosage compensation between sexes, fundamental for embryo viability. A previous study using single-cell RNA-sequencing (scRNA-seq) data proposed that female human preimplantation embryos achieve dosage compensation by downregulating both Xs, a phenomenon named dampening of X expression. Using a novel pipeline on those data, we identified a decrease in the proportion of biallelically expressed X-linked genes during development, consistent with XCI. Moreover, we show that while the expression sum of biallelically expressed X-linked genes decreases with embryonic development, their median expression remains constant, rejecting the hypothesis of X dampening. In addition, analyses of a different dataset of scRNA-seq suggest the appearance of X-linked monoallelic expression by the late blastocyst stage in females, another hallmark of initiation of XCI. Finally, we addressed the issue of dosage compensation between the single active X and autosomes in males and females for the first time during human preimplantation development, showing emergence of X to autosome dosage compensation by the upregulation of the active X chromosome in both male and female embryonic stem cells. Our results show compelling evidence of an early process of X chromosome inactivation during human preimplantation development.

Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1).

Abstract: X chromosome inactivation is an epigenetic dosage compensation mechanism in female mammals driven by the long noncoding RNA, Xist. Although recent genomic and proteomic approaches have provided a more global view of Xist's function, how Xist RNA localizes to the inactive X chromosome (Xi) and spreads in cis remains unclear. Here, we report that the CDKN1-interacting zinc finger protein CIZ1 is critical for localization of Xist RNA to the Xi chromosome territory. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. CIZ1 interacts with a specific region within Xist exon 7-namely, the highly repetitive Repeat E motif. Using genetic analysis, we show that loss of CIZ1 or deletion of Repeat E in female cells phenocopies one another in causing Xist RNA to delocalize from the Xi and disperse into the nucleoplasm. Interestingly, this interaction is exquisitely sensitive to CIZ1 levels, as overexpression of CIZ1 likewise results in Xist delocalization. As a consequence, this delocalization is accompanied by a decrease in H3K27me3 on the Xi. Our data reveal that CIZ1 plays a major role in ensuring stable association of Xist RNA within the Xi territory.

Convergent origination of a Drosophila-like dosage compensation mechanism in a reptile lineage

Abstract: Sex chromosomes differentiated from different ancestral autosomes in various vertebrate lineages. Here, we trace the functional evolution of the XY Chromosomes of the green anole lizard (Anolis carolinensis), on the basis of extensive high-throughput genome, transcriptome and histone modification sequencing data and revisit dosage compensation evolution in representative mammals and birds with substantial new expression data. Our analyses show that Anolis sex chromosomes represent an ancient XY system that originated at least ≈160 million years ago in the ancestor of Iguania lizards, shortly after the separation from the snake lineage. The age of this system approximately coincides with the ages of the avian and two mammalian sex chromosomes systems. To compensate for the almost complete Y Chromosome degeneration, X-linked genes have become twofold up-regulated, restoring ancestral expression levels. The highly efficient dosage compensation mechanism of Anolis represents the only vertebrate case identified so far to fully support Ohno's original dosage compensation hypothesis. Further analyses reveal that X up-regulation occurs only in males and is mediated by a male-specific chromatin machinery that leads to global hyperacetylation of histone H4 at lysine 16 specifically on the X Chromosome. The green anole dosage compensation mechanism is highly reminiscent of that of the fruit fly, Drosophila melanogaster Altogether, our work unveils the convergent emergence of a Drosophila-like dosage compensation mechanism in an ancient reptilian sex chromosome system and highlights that the evolutionary pressures imposed by sex chromosome dosage reductions in different amniotes were resolved in fundamentally different ways.

The Evolution of Sex Chromosomes and Dosage Compensation in Plants.

Abstract: Plant sex chromosomes can be vastly different from those of the few historical animal model organisms from which most of our understanding of sex chromosome evolution is derived. Recently, we have seen several advancements from studies on green algae, brown algae, and land plants that are providing a broader understanding of the variable ways in which sex chromosomes can evolve in distant eukaryotic groups. Plant sex-determining genes are being identified and, as expected, are completely different from those in animals. Species with varying levels of differentiation between the X and Y have been found in plants, and these are hypothesized to be representing different stages of sex chromosome evolution. However, we are also finding that sex chromosomes can remain morphologically unchanged over extended periods of time. Where degeneration of the Y occurs, it appears to proceed similarly in plants and animals. Dosage compensation (a phenomenon that compensates for the consequent loss of expression from the Y) has now been documented in a plant system, its mechanism, however, remains unknown. Research has also begun on the role of sex chromosomes in sexual conflict resolution, and it appears that sex-biased genes evolve similarly in plants and animals, although the functions of these genes remain poorly studied. Because the difficulty in obtaining sex chromosome sequences is increasingly being overcome by methodological developments, there is great potential for further discovery within the field of plant sex chromosome evolution.

Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes.

Abstract: Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, we present an approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique. Our screen of chromosome I suggests that dosage-compensated genes constitute approximately 10% of the genome and consist predominantly of subunits of multi-protein complexes. Importantly, because subunit levels are regulated in a stoichiometry-dependent manner, dosage compensation plays a crucial role in maintaining subunit stoichiometries. Indeed, we observed changes in the levels of a complex when its subunit stoichiometries were perturbed. We further analyzed compensation mechanisms using a proteasome-defective mutant as well as ribosome profiling, which provided strong evidence for compensation by ubiquitin-dependent degradation but not reduced translational efficiency. Thus, our study provides a systematic understanding of dosage compensation and highlights that this post-translational regulation is a critical aspect of robustness in cellular systems.

Systematic Analysis of the Determinants of Gene Expression Noise in Embryonic Stem Cells

Abstract: Isogenic cells in a common environment show substantial cell-to-cell variation in gene expression, often referred to as "expression noise." Here, we use multiple single-cell RNA-sequencing datasets to identify features associated with high or low expression noise in mouse embryonic stem cells. These include the core promoter architecture of a gene, with CpG island promoters and a TATA box associated with low and high noise, respectively. High noise is also associated with "conflicting" chromatin states-the absence of transcription-associated histone modifications or the presence of repressive ones in active genes. Genes regulated by pluripotency factors through super-enhancers show high and correlated expression variability, consistent with fluctuations in the pluripotent state. Together, our results provide an integrated view of how core promoters, chromatin, regulation, and pluripotency fluctuations contribute to the variability of gene expression across individual stem cells.

Origin of Amniote Sex Chromosomes: An Ancestral Super-Sex Chromosome, or Common Requirements?

Abstract: The diversity of sex chromosomes among amniotes is the product of independent evolution of different systems in different lineages, defined by novel sex-determining genes. Convergent evolution is very common, suggesting that some genes are particularly adept at taking on a sex-determining role. Comparative gene mapping, and more recently whole genome sequencing, have now turned up other surprising relationships; different regions of the amniote genome that have become sex determining in some taxa seem to share synteny, or share sequence, in others. Is this, after all, evidence that these regions were once linked in a super-sex chromosome that underwent multiple fission in different ways in different amniote lineages? Or does it signify that special properties of sex chromosomes (paucity of active genes, low recombination, epigenetic regulation to achieve dosage compensation) predispose particular chromosomes to a sex-determining role?

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Abstract: A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.

Contribution of epigenetic landscapes and transcription factors to X-chromosome reactivation in the inner cell mass.

Abstract: X-chromosome inactivation is established during early development. In mice, transcriptional repression of the paternal X-chromosome (Xp) and enrichment in epigenetic marks such as H3K27me3 is achieved by the early blastocyst stage. X-chromosome inactivation is then reversed in the inner cell mass. The mechanisms underlying Xp reactivation remain enigmatic. Using in vivo single-cell approaches (allele-specific RNAseq, nascent RNA-fluorescent in situ hybridization and immunofluorescence), we show here that different genes are reactivated at different stages, with more slowly reactivated genes tending to be enriched in H3meK27. We further show that in UTX H3K27 histone demethylase mutant embryos, these genes are even more slowly reactivated, suggesting that these genes carry an epigenetic memory that may be actively lost. On the other hand, expression of rapidly reactivated genes may be driven by transcription factors. Thus, some X-linked genes have minimal epigenetic memory in the inner cell mass, whereas others may require active erasure of chromatin marks.

Purifying and Positive Selection Influence Patterns of Gene Loss and Gene Expression in the Evolution of a Plant Sex Chromosome System.

Abstract: Sex chromosomes are unique regions of the genome, with a host of properties that distinguish them from autosomes and from each other. Although there is extensive theory describing sex chromosome formation and subsequent degeneration of the Y chromosome, the relative importance of processes governing degeneration is poorly understood. In particular, it is not known whether degeneration occurs solely as a direct result of inefficient selection due to loss of recombination, or whether adaptive gene silencing on the Y chromosome results in most degeneration occurring neutrally. We used comparative transcriptome data from two related annual plants with highly heteromorphic sex chromosomes, Rumex rothschildianus and Rumex hastatulus, to investigate the patterns and processes underlying Y chromosome degeneration. The rate of degeneration varied greatly between the two species. In R. rothschildianus, we infer widespread gene loss, higher than previously reported for any plant. Gene loss was not random: genes with lower constraint and those not expressed during the haploid phase were more likely to be lost. There was indirect evidence of adaptive evolution on the Y chromosome from the over-expression of Y alleles in certain genes with sex-biased gene expression. There was no complete dosage compensation, but there was evidence for targeted dosage compensation occurring in more selectively constrained genes. Overall, our results are consistent with selective interference playing the dominant role in the degeneration of the Y chromosome, rather than adaptive gene silencing.

Sex Reversal and Comparative Data Undermine the W Chromosome and Support Z-linked DMRT1 as the Regulator of Gonadal Sex Differentiation in Birds

Abstract: The exact genetic mechanism regulating avian gonadal sex differentiation has not been completely resolved. The most likely scenario involves a dosage mechanism, whereby the Z-linked DMRT1 gene triggers testis development. However, the possibility still exists that the female-specific W chromosome may harbor an ovarian determining factor. In this study, we provide evidence that the universal gene regulating gonadal sex differentiation in birds is Z-linked DMRT1 and not a W-linked (ovarian) factor. Three candidate W-linked ovarian determinants are HINTW, female-expressed transcript 1 (FET1), and female-associated factor (FAF). To test the association of these genes with ovarian differentiation in the chicken, we examined their expression following experimentally induced female-to-male sex reversal using the aromatase inhibitor fadrozole (FAD). Administration of FAD on day 3 of embryogenesis induced a significant loss of aromatase enzyme activity in female gonads and masculinization. However, expression levels of HINTW, FAF, and FET1 were unaltered after experimental masculinization. Furthermore, comparative analysis showed that FAF and FET1 expression could not be detected in zebra finch gonads. Additionally, an antibody raised against the predicted HINTW protein failed to detect it endogenously. These data do not support a universal role for these genes or for the W sex chromosome in ovarian development in birds. We found that DMRT1 (but not the recently identified Z-linked HEMGN gene) is male upregulated in embryonic zebra finch and emu gonads, as in the chicken. As chicken, zebra finch, and emu exemplify the major evolutionary clades of birds, we propose that Z-linked DMRT1, and not the W sex chromosome, regulates gonadal sex differentiation in birds.

Cognitive, behavioral, and neural consequences of sex chromosome aneuploidy.

Abstract: The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. There are relatively specific effects of X-linked genes on social cognition, language, emotional regulation, visuospatial, and numerical skills. Many human X-linked genes outside the X–Y pairing pseudoautosomal regions escape X-inactivation. Dosage differences in the expression of such genes (which constitute at least 15% of the total) are likely to play an important role in male–female neural differentiation, and in cognitive deficits and behavioral characteristics, particularly in the realm of social communication, that are associated with sex chromosome aneuploidies. © 2016 Wiley Periodicals, Inc.

Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation.

Abstract: Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes. In mouse, but not opossum and chicken, sex bias is coordinated across tissues such that autosomal testis-biased miRNAs tend to be somatically male-biased, whereas autosomal ovary-biased miRNAs are female-biased, possibly due to broad hormonal control. In chicken, which has a Z/W sex chromosome system, expression output of genes on the Z Chromosome is expected to be male-biased, since there is no global dosage compensation mechanism that restores expression in ZW females after almost all genes on the W Chromosome decayed. Nevertheless, we found that the dominant liver miRNA, miR-122-5p, is Z-linked but expressed in an unbiased manner, due to the unusual retention of a W-linked copy. Another Z-linked miRNA, the male-biased miR-2954-3p, shows conserved preference for dosage-sensitive genes on the Z Chromosome, based on computational and experimental data from chicken and zebra finch, and acts to equalize male-to-female expression ratios of its targets. Unexpectedly, our findings thus establish miRNA regulation as a novel gene-specific dosage compensation mechanism.

Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP

Abstract: The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3-histone4 promoter direct HLB formation in Drosophila In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation. We demonstrated previously that CLAMP also promotes the formation of another domain of coordinated gene regulation: the dosage-compensated male X chromosome. Therefore, CLAMP binding to GA repeat motifs promotes the formation of two distinct domains of coordinated gene activation located at different places in the genome.

PAR-TERRA directs homologous sex chromosome pairing

Abstract: In mammals, homologous chromosomes rarely pair outside meiosis. One exception is the X chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem (ES) cells. The subtelomeric, pseudoautosomal regions (PARs) of the two sex chromosomes (X and Y) also undergo pairing in both female and male cells. PARs transcribe a class of telomeric RNA, dubbed PAR-TERRA, which accounts for a vast majority of all TERRA transcripts. PAR-TERRA binds throughout the genome, including to the PAR and Xic. During X-chromosome pairing, PAR-TERRA anchors the Xic to the PAR, creating a 'tetrad' of pairwise homologous interactions (Xic-Xic, PAR-PAR, and Xic-PAR). Xic pairing occurs within the tetrad. Depleting PAR-TERRA abrogates pairing and blocks initiation of XCI, whereas autosomal PAR-TERRA induces ectopic pairing. We propose a 'constrained diffusion model' in which PAR-TERRA creates an interaction hub to guide Xic homology searching during XCI.

Global Dosage Compensation Is Ubiquitous in Lepidoptera, but Counteracted by the Masculinization of the Z Chromosome.

Abstract: While chromosome-wide dosage compensation of the X chromosome has been found in many species, studies in ZW clades have indicated that compensation of the Z is more localized and/or incomplete. In the ZW Lepidoptera, some species show complete compensation of the Z chromosome, while others lack full equalization, but what drives these inconsistencies is unclear. Here, we compare patterns of male and female gene expression on the Z chromosome of two closely related butterfly species, Papilio xuthus and Papilio machaon, and in multiple tissues of two moths species, Plodia interpunctella and Bombyx mori, which were previously found to differ in the extent to which they equalize Z-linked gene expression between the sexes. We find that, while some species and tissues seem to have incomplete dosage compensation, this is in fact due to the accumulation of male-biased genes and the depletion of female-biased genes on the Z chromosome. Once this is accounted for, the Z chromosome is fully compensated in all four species, through the up-regulation of Z expression in females and in some cases additional down-regulation in males. We further find that both sex-biased genes and Z-linked genes have increased rates of expression divergence in this clade, and that this can lead to fast shifts in patterns of gene expression even between closely related species. Taken together, these results show that the uneven distribution of sex-biased genes on sex chromosomes can confound conclusions about dosage compensation and that Z chromosome-wide dosage compensation is not only possible but ubiquitous among Lepidoptera.

X chromosome inactivation: new players in the initiation of gene silencing.

Abstract: X chromosome inactivation (XCI) is a dosage compensation process that was adopted by female mammals to balance gene dosage between XX females and XY males. XCI starts with the upregulation of the non-coding RNA Xist, after which most X-linked genes are silenced and acquire a repressive chromatin state. Even though the chromatin marks of the inactive X have been fairly well described, the mechanisms responsible for the initiation of XCI remain largely unknown. In this review, we discuss recent developments that revealed unexpected factors playing a role in XCI and that might be of crucial importance to understand the mechanisms responsible for the very first steps of this chromosome-wide gene-silencing event.

Global Analysis of Gene Expression in Response to Whole-Chromosome Aneuploidy in Hexaploid Wheat.

Abstract: Aneuploidy, a condition of unbalanced chromosome content, represents a large-effect mutation that bears significant relevance to human health and microbe adaptation. As such, extensive studies of aneuploidy have been conducted in unicellular model organisms and cancer cells. Aneuploidy also frequently is associated with plant polyploidization, but its impact on gene expression and its relevance to polyploid genome evolution/functional innovation remain largely unknown. Here, we used a panel of diverse types of whole-chromosome aneuploidy of hexaploid wheat (Triticum aestivum), all under the common genetic background of cv Chinese Spring, to systemically investigate the impact of aneuploidy on genome-, subgenome-, and chromosome-wide gene expression. Compared with prior findings in haploid or diploid aneuploid systems, we unravel additional and novel features of alteration in global gene expression resulting from the two major impacts of aneuploidy, cis- and trans-regulation, as well as dosage compensation. We show that the expression-altered genes map evenly along each chromosome, with no evidence for coregulating aggregated expression domains. However, chromosomes and subgenomes in hexaploid wheat are unequal in their responses to aneuploidy with respect to the number of genes being dysregulated. Strikingly, homeologous chromosomes do not differ from nonhomologous chromosomes in terms of aneuploidy-induced trans-acting effects, suggesting that the three constituent subgenomes of hexaploid wheat are largely uncoupled at the transcriptional level of gene regulation. Together, our findings shed new insights into the functional interplay between homeologous chromosomes and interactions between subgenomes in hexaploid wheat, which bear implications to further our understanding of allopolyploid genome evolution and efforts in breeding new allopolyploid crops.

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation.

Abstract: X chromosome dosage compensation in Drosophila requires chromosome-wide coordination of gene activation. The male-specific lethal dosage compensation complex (DCC) identifies and binds to X-chromosomal high-affinity sites (HAS) from which it boosts transcription. A sub-class of HAS, PionX sites, represent first contacts on the X. Here, we explored the chromosomal interactions of representative PionX sites by high-resolution 4C and determined the global chromosome conformation by Hi-C in sex-sorted embryos. Male and female X chromosomes display similar nuclear architecture, concordant with clustered, constitutively active genes. PionX sites, like HAS, are evenly distributed in the active compartment and engage in short- and long-range interactions beyond compartment boundaries. Long-range, inter-domain interactions between DCC binding sites are stronger in males, suggesting that the complex refines chromatin organization. By de novo induction of DCC in female cells, we monitored the extent of activation surrounding PionX sites. This revealed a remarkable range of DCC action not only in linear proximity, but also at megabase distance if close in space, suggesting that DCC profits from pre-existing chromosome folding to activate genes.