Multi-condition and multi-modal temporal profile inference during mouse embryonic development.

The emergence of single-cell time-series datasets enables modeling of changes in various types of cellular profiles over time. However, due to the disruptive nature of single-cell measurements, it is impossible to capture the full temporal trajectory of a particular cell. Furthermore, single-cell profiles can be collected at mismatched time points across different conditions (e.

KDM6A facilitates Xist upregulation at the onset of X inactivation.

X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNA on the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions.

CTCF-mediated insulation and chromatin environment modulate escape from X inactivation.

Background: The number and escape levels of genes that escape X chromosome inactivation (XCI) in female somatic cells vary among tissues and cell types, potentially contributing to specific sex differences. Here we investigate the role of CTCF, a master chromatin conformation regulator, in regulating escape from XCI. CTCF binding profiles and epigenetic features were systematically examined at constitutive and facultative escape genes using mouse allelic systems to distinguish the inactive X (Xi) and active X (Xa) chromosomes.

Sex-biased and parental allele-specific gene regulation by KDM6A.

Background: KDM6A is a demethylase encoded by a gene with female-biased expression due to escape from X inactivation. Its main role is to facilitate gene expression through removal of the repressive H3K27me3 mark, with evidence of some additional histone demethylase-independent functions. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in cancer.

Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome.

Firre encodes a lncRNA involved in nuclear organization. Here, we show that Firre RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of the Polycomb repressive complexes.

Genotoxicity of (+)- and (-)-usnic acid in mice.

Usnic acid, which is the most widespread and well-studied secondary lichen compound, has antibacterial and cytotoxic effects. Usnic acid is present in lichens as the (+)- and (-)-enantiomers, which have different biological activities. We used a DNA-comet assay to determine the genotoxic effect of (+)- and (-)-usnic acid in the liver and kidney cells of mice.

CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer.

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in , which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of haploinsufficiency.

A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility.

We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide chromatin accessibility in ∼100,000 single cells from 13 adult mouse tissues. We identify 85 distinct patterns of chromatin accessibility, most of which can be assigned to cell types, and ∼400,000 differentially accessible elements. We use these data to link regulatory elements to their target genes, to define the transcription factor grammar specifying each cell type, and to discover in vivo correlates of heterogeneity in accessibility within cell types.

Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by insufficient epigenetic repression of D4Z4 macrosatellite repeat where DUX4, an FSHD causing gene is embedded. There are two forms of FSHD, FSHD1 with contraction of D4Z4 repeat and FSHD2 with chromatin compaction defects mostly due to SMCHD1 mutation. Previous reports showed DUX4-induced gene expression changes as well as changes in microRNA expression in FSHD muscle cells.

Orientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome.

The mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts, separated by a hinge region. Using Hi-C in edited mouse cells with allelic deletions or inversions within the hinge, here we show that the conserved Dxz4 locus is necessary to maintain this bipartite structure. Dxz4 orientation controls the distribution of contacts on the Xi, as shown by a massive reversal in long-range contacts after Dxz4 inversion.

Pro/Antigenotoxic Activity of Usnic Acid Enantiomers In Vitro.

The effect of usnic acid enantiomers on the genotoxic effects of dioxidine and methyl methanesulfonate was studied in vitro in human peripheral blood lymphocytes by the DNA comet method. We found that usnic acid enantiomers in a concentration range of 0.01-1.

Mental state assessment of recipients in the IVF donor programs and psychotherapeutic methods of its correction.

The management of infertility with assisted reproductive technologies (ART) could solve a medical problem but still leave psychosocial problems, associated with both long-term infertility and specific treatment, unaddressed in a number of cases. Evaluation of the mental state of recipients in the IVF donor programs and its dynamics when mid-term multimodal psychotherapy has been used. The study was conducted in the Family Medicine Center - an ART clinic of the city of Ekaterinburg, Russia between 2016 and 2017.

SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is in most cases caused by a contraction of the D4Z4 macrosatellite repeat on chromosome 4 (FSHD1) or by mutations in the SMCHD1 or DNMT3B gene (FSHD2). Both situations result in the incomplete epigenetic repression of the D4Z4-encoded retrogene DUX4 in somatic cells, leading to the aberrant expression of DUX4 in the skeletal muscle. In mice, Smchd1 regulates chromatin repression at different loci, having a role in CpG methylation establishment and/or maintenance.

GENOTOXIC EFFECT OF USNIC ACID ENANTIOMERS IN VITRO IN HUMAN PERIPHERAL BLOOD LYMPHOCYTES.

Cytotoxic and genotoxic effect of (+) and (–) enantiomers of usnic acid in human peripheral blood lymphocytes studed. We have shown that the studied usnic acid enantiomers in concentrations of 0.04—0.

Effect of Uranium and Thorium Radionuclides on Biochemical Characteristics of Duschekia fruticosa in "Soil-Plant" System.

The biochemical characteristics of Duschekiafruticosa, grown for a long time under a variety of exposure doses of natural background radiation (up to 150 μR/h) was studied. Uranium was found to make the dominant contribution to the y-background exposure doses. The pH-values and the content of organic matter in soils within the surveyed territory remained unchanged.

DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the DUX4 transcription factor in skeletal muscle. The DUX4 retrogene is encoded in the D4Z4 macrosatellite repeat array, and smaller array size or a mutation in the SMCHD1 gene results in inefficient epigenetic repression of DUX4 in skeletal muscle, causing FSHD1 and FSHD2, respectively. Previously we showed that the entire D4Z4 repeat is bi-directionally transcribed with the generation of small si- or miRNA-like fragments and suggested that these might suppress DUX4 expression through the endogenous RNAi pathway.

The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation.

Background: In mammals, X chromosome genes are present in one copy in males and two in females. To balance the dosage of X-linked gene expression between the sexes, one of the X chromosomes in females is silenced. X inactivation is initiated by upregulation of the lncRNA (long non-coding RNA) Xist and recruitment of specific chromatin modifiers.

CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.

Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established.

Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds.

Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation.

Purpose Of Review: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder.

Recent Findings: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1).

Asymmetric bidirectional transcription from the FSHD-causing D4Z4 array modulates DUX4 production.

Facioscapulohumeral Disease (FSHD) is a dominantly inherited progressive myopathy associated with aberrant production of the transcription factor, Double Homeobox Protein 4 (DUX4). The expression of DUX4 depends on an open chromatin conformation of the D4Z4 macrosatellite array and a specific haplotype on chromosome 4. Even when these requirements are met, DUX4 transcripts and protein are only detectable in a subset of cells indicating that additional constraints govern DUX4 production.

Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos.

CTCF is a highly conserved, multifunctional zinc finger protein involved in critical aspects of gene regulation including transcription regulation, chromatin insulation, genomic imprinting, X-chromosome inactivation, and higher order chromatin organization. Such multifunctional properties of CTCF suggest an essential role in development. Indeed, a previous report on maternal depletion of CTCF suggested that CTCF is essential for pre-implantation development.

CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG/polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription coactivator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated.

Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.

Each unit of the D4Z4 macrosatellite repeat contains a retrotransposed gene encoding the DUX4 double-homeobox transcription factor. Facioscapulohumeral dystrophy (FSHD) is caused by deletion of a subset of the D4Z4 units in the subtelomeric region of chromosome 4. Although it has been reported that the deletion of D4Z4 units induces the pathological expression of DUX4 mRNA, the association of DUX4 mRNA expression with FSHD has not been rigorously investigated, nor has any human tissue been identified that normally expresses DUX4 mRNA or protein.