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Concept: X-inactivation


Epigenome mapping consortia are generating resources of tremendous value for studying epigenetic regulation. To maximize their utility and impact, new tools are needed that facilitate interactive analysis of epigenome datasets. Here we describe EpiExplorer, a web tool for exploring genome and epigenome data on a genomic scale. We demonstrate EpiExplorer’s utility by describing a hypothesis-generating analysis of DNA hydroxymethylation in relation to public reference maps of the human epigenome. All EpiExplorer analyses are performed dynamically within seconds, using an efficient and versatile text indexing scheme that we introduce to bioinformatics. EpiExplorer is available at

Concepts: DNA, Gene expression, Histone, Human Genome Project, DNA methylation, Methylation, X-inactivation, Computational epigenetics


Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.

Concepts: DNA, Gene, Genetics, Gene expression, Molecular biology, Epigenetics, Autism, X-inactivation


During interphase, the inactive X chromosome (Xi) is largely transcriptionally silent and adopts an unusual 3D configuration known as the “Barr body.” Despite the importance of X chromosome inactivation, little is known about this 3D conformation. We recently showed that in humans the Xi chromosome exhibits three structural features, two of which are not shared by other chromosomes. First, like the chromosomes of many species, Xi forms compartments. Second, Xi is partitioned into two huge intervals, called “superdomains,” such that pairs of loci in the same superdomain tend to colocalize. The boundary between the superdomains lies near DXZ4, a macrosatellite repeat whose Xi allele extensively binds the protein CCCTC-binding factor. Third, Xi exhibits extremely large loops, up to 77 megabases long, called “superloops.” DXZ4 lies at the anchor of several superloops. Here, we combine 3D mapping, microscopy, and genome editing to study the structure of Xi, focusing on the role of DXZ4 We show that superloops and superdomains are conserved across eutherian mammals. By analyzing ligation events involving three or more loci, we demonstrate that DXZ4 and other superloop anchors tend to colocate simultaneously. Finally, we show that deleting DXZ4 on Xi leads to the disappearance of superdomains and superloops, changes in compartmentalization patterns, and changes in the distribution of chromatin marks. Thus, DXZ4 is essential for proper Xi packaging.

Concepts: DNA, Gene, Cell nucleus, Chromosome, X chromosome, X-inactivation, XY sex-determination system, Barr body


Down’s syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down’s syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a ‘chromosome 21 Barr body’. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of ‘chromosome therapy’.

Concepts: DNA, Gene, Genetics, Gene expression, Histone, RNA, Chromosome, X-inactivation


Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genome-wide DNA demethylation to reset the epigenome for totipotency. Here, we demonstrate that erasure of CpG methylation (5mC) in PGCs occurs via conversion to 5-hydroxymethylcytosine (5hmC), driven by high levels of TET1 and TET2. Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5-E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, we identify rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.

Concepts: DNA, Gene, Gene expression, Histone, Epigenetics, DNA methylation, Methylation, X-inactivation


Esquilin JM, Takemoto CM, Green, NS. Female factor IX deficiency due to maternally inherited X-inactivation. X-chromosome inactivation is normally a random event that is regulated by the X chromosome itself. Rarely, females are affected by X-linked disorders from extremely skewed X-chromosome inactivation. Here, we report a family with hemophilia B with female expression through inherited X skewing that appears to be independent of either X chromosome. This finding suggests the possibility of a dominant autosomal contribution to inherited skewed X inactivation.

Concepts: DNA, Female, Chromosome, Gender, X chromosome, X-inactivation, Barr body, Skewed X-inactivation


Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom Fabry disease was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known about other members affected respectively by fucosidosis or Mucopolysaccharidosis I (MPSI) Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study demonstrates that the risk for more than one lysosomal storage disorder can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present due to the random X-chromosome inactivation.

Concepts: Lysosomal storage disease, Fabry disease, Mucopolysaccharidosis, Lysosomal storage diseases, Hunter syndrome, Sanfilippo syndrome, Mucolipidosis, X-inactivation


Dosage compensation of X-linked gene products between the sexes in therians has culminated in the inactivation of one of the two X chromosomes in female cells. Over the years, the mouse has been the preferred animal model to study this X-chromosome inactivation (XCI) process in placental mammals (eutherians). Similar to the imprinted inactivation of the paternally inherited X chromosome (Xp) in marsupials (methatherians), the Xp is inactivated during early mouse development. In this eutherian model, cell derivatives of the primitive endoderm (PE) and trophectoderm (TE) will continue to display this imprinted form of XCI. Cells developing from the mouse epiblast will reactivate the Xp, and subsequently initiate XCI of either the Xp or the maternally inherited Xm, in a random manner. Examination of XCI in other eutherians and in metatherians, however, indicates clear differences in the form and timing of XCI. This review highlights and discusses imprinted and random XCI from such a comparative viewpoint.

Concepts: Gene, Chromosome, Mammal, X chromosome, X-inactivation, Eutheria, Metatheria, Theria


X and Y chromosomal variations including tetrasomy and pentasomy conditions are rare and occur in 1:18,000-1:100,000 male births. The most common sex chromosome aneuploidy is 47, XXY for which there is a rich literature delineating the physical and neurobehavioral phenotype. Although the more complex chromosome aneuploidies 48, XXYY, 48, XXXY, and 49, XXXXY are often compared with 47, XXY (Klinefelter syndrome) because of shared features including tall stature and hypergonadotropic hypogonadism, there is a wider spectrum of physical and cognitive abilities that have recently been delineated. The phenotypic presentation of the boys with more severe aneuploidy shares some characteristics with 47, XXY, but there are also other unique and distinctive features. Previously unappreciated intact nonverbal skills have been demonstrated in association with severe developmental dyspraxia. MRI findings of white matter hyperintensities may underlie cognitive deficits and deserve further study. This report discusses what is known about clinical variability in the XY syndromes collectively evaluated through careful multidisciplinary clinical evaluation including the clinical and neurobehavioral aspects of these conditions. Variability in clinical and cognitive functioning may reflect skewed X inactivation, mosaicism, or epigenetic factors that warrant further investigation. © 2013 Wiley Periodicals, Inc.

Concepts: Chromosome, Klinefelter's syndrome, Aneuploidy, Y chromosome, X chromosome, X-inactivation, Mosaic, Tetrasomy


Epigenetics refers to chemical modifications leading to changes in gene expression without any alteration of the DNA structure. We suggest ways through which epigenetic mechanisms might contribute to alter developmental trajectories in preterm infants. Although theoretical and methodological issues still need to be addressed, we discuss how epigenetics might be an emergent research field with potential innovative insights for researchers and clinicians involved in the neonatal care of preterm infants.

Concepts: DNA, Scientific method, Gene, Gene expression, Epigenetics, DNA methylation, X-inactivation, Research and development