Integrative DNA Methylation and Gene Expression Analyses Identify DNA Packaging and Epigenetic Regulatory Genes Associated with Low Motility Sperm

In previous studies using candidate gene approaches, low sperm count (oligospermia) has been associated with altered sperm mRNA content and DNA methylation in both imprinted and non-imprinted genes. We performed a genome-wide analysis of sperm DNA methylation and mRNA content to test for associations with sperm function. (NCBI 1788). There was a trend among altered expression of these epigenetic regulatory genes and RPMM DNA methylation class.Using integrative genome-wide approaches we identified CpG methylation profiles and mRNA alterations associated with low sperm motility

Assisted reproduction treatment and epigenetic inheritance

Background: The subject of epigenetic risk of assisted reproduction treatment (ART), initiated by reports on an increase of children with the Beckwith–Wiedemann imprinting disorder, is very topical. Hence, there is a growing literature, including mouse studies. Methods: In order to gain information on transgenerational epigenetic inheritance and epigenetic effects induced by ART, literature databases were searched for papers on this topic using relevant keywords. Results: At the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are convincingly observed in mice, especially for placenta, and seem more frequent than in humans. Data generally provide a warning as to the use of ovulation induction and in vitro culture. In human sperm from compromised spermatogenesis, sequence-specific DNA hypomethylation is observed repeatedly. Transmittance of sperm and oocyte DNA methylation defects is possible but, as deduced from the limited data available, largely prevented by selection of gametes for ART and/or non-viability of the resulting embryos. Some evidence indicates that subfertility itself is a risk factor for imprinting diseases. As in mouse, physiological effects from ART are observed in humans. In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found. In the mouse, a broader range of CpG sequences has not yet been studied. Also, a multigeneration study of systematic ART on epigenetic parameters is lacking. Conclusions: The field of epigenetic inheritance within the lifespan of an individual and between generations (via mitosis and meiosis, respectively) is growing, driven by the expansion of chromatin research. ART can induce epigenetic variation that might be transmitted to the next generation

Severe XIST hypomethylation clearly distinguishes (SRY+) 46,XX-maleness from Klinefelter syndrome

Objective46,XX-maleness affects 1 in 20 000 live male newborns resulting in infertility and hypergonadotrophic hypogonadism. Although the phenotypes of XX-males have been well described, the molecular nature of the X chromosomes remains elusive. We assessed the X inactivation status by DNA methylation analysis of four informative loci and compared those to Klinefelter syndrome (KS) and Turner syndrome.Design and methodsPatient cohort consisted of ten sex-determining region of the Y (SRY+) XX-males, two (SRY−) XX-males, ten 47,XXY Klinefelter men, six 45,X Turner females and ten male and female control individuals each. Methylation analysis was carried out by bisulphite sequencing of DNA from peripheral blood lymphocytes analysing X-inactive-specific transcript (XIST), phosphoglycerate kinase 1 (PGK1), ferritin, heavy peptide-like 17 (FTHL17) and short stature homeobox (SHOX).ResultsXIST methylation was 18% in (SRY+) XX-males, and thus they were severely hypomethylated compared to (SRY−) XX-males (48%; P&lt;0.01), Klinefelter men (44%; P&lt;0.01) and female controls (47%; P&lt;0.01). Turner females and male controls displayed a high degree of XIST methylation of 98 and 94% respectively. Methylation of PGK1, undergoing X inactivation, was not significantly reduced in (SRY+) XX-males compared to female controls in spite of severe XIST hypomethylation (51 vs 69%; P&gt;0.05). FTHL17, escaping X inactivation, but undergoing cell-type-specific inactivation was similarly methylated in XX-males (89%), KS patients (87%) and female controls (90%). SHOX, an X inactivation escapee located in the pseudoautosomal region, displays similarly low degrees of methylation for XX-males (7%), KS patients (7%) and female controls (9%).ConclusionsXIST hypomethylation clearly distinguishes (SRY+) XX-males from Klinefelter men. It does not, however, impair appropriate epigenetic regulation of representative X-linked loci.</jats:sec

Male 41, XXY* mice as a model for Klinefelter syndrome: Hyperactivation of Leydig cells

Sex chromosome imbalance in males is linked to a supernumerary X chromosome, a condition resulting in Klinefelter syndrome (KS; 47, XXY). KS patients suffer from infertility, hypergonadotropic hypogonadism, and cognitive impairments. Mechanisms of KS pathophysiology are poorly understood and require further exploration using animal models. Therefore, we phenotypically characterized 41, XX(Y)* mice of different ages, evaluated observed germ cell loss, studied X-inactivation, and focused on the previously postulated impaired Leydig cell maturation and function as a possible cause of the underandrogenization seen in KS. Xist methylation analysis revealed normal X-chromosome inactivation similar to that seen in females. Germ cell loss was found to be complete and to occur during the peripubertal phase. Significantly elevated FSH and LH levels were persistent in 41, XX(Y)* mice of different ages. Although Leydig cell hyperplasia was prominent, isolated XX(Y)* Leydig cells showed a mature mRNA expression profile and a significantly higher transcriptional activity compared with controls. Stimulation of XX(Y)* Leydig cells in vitro by human chorionic gonadotropin indicated a mature LH receptor whose maximal response exceeded that of control Leydig cells. The hyperactivity of Leydig cells seen in XX(Y)* mice suggests that the changes in the endocrine milieu observed in KS is not due to impaired Leydig cell function. We suggest that the embedding of Leydig cells into the changed testicular environment in 41 XX(Y)* males as such influences their endocrine function

Severity of Psychopathy in a Community-Recruited Sample is Indexed by Increased Social Discounting

Psychopathy is a personality construct characterized by boldness, disinhibition, insensitivity to others’ suffering or distress, and persistent engagement in behaviors that harm others. These combined features suggest that highly psychopathic people may place much less subjective weight on others’ outcomes relative to their own. We therefore assessed social discounting, which indexes how the subjective value of others’ outcomes declines as a function of social distance, in a demographically diverse community sample of very-high psychopathy adults (above the 95th percentile of TriPM scorers; n = 288), as well as a sample of demographically similar controls (n = 427), who also reported antisocial and criminal behavior. Results show robust increases in social discounting as psychopathy increases, and that reduced subjective valuation of others’ outcomes partially mediates the group differences in antisocial behavior. These insights emphasize the importance of understanding how psychopathic traits manifest in the community and underscore how diminished valuation of others’ outcomes represents an important mechanism driving maladaptive behaviors. and highlight the need for interventions aimed at increasing how others’ outcomes are valued