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DNA methylation and DNA methyltransferases are essential for spermatogenesis. Mutations in the DNA methyltransferase Dnmt1 gene exert a paternal effect on epigenetic states and phenotypes of offspring, suggesting that DNMT1 is important for the epigenetic remodeling of the genome that takes place during spermatogenesis. However, the specific role of DNMT1 in spermatogenesis and the establishment of genomic imprints in the male germ line remains elusive. To further characterize the effect of DNMT1 deficiency on the resetting of methylation imprints during spermatogenesis, we analyzed the methylation profiles of imprinted regions in the spermatozoa of mice that were heterozygous for a Dnmt1 loss-of- function mutation. The mutation did not affect the H19 or IG differentially methylated regions (DMRs) that are usually highly methylated but led to a partial hypermethylation of the Snrpn DMR, a region that should normally be unmethylated in mature spermatozoa. This defect does not appear in mouse models with mutations in Dnmt3a and Mthfr genes and, therefore, it is specific for the Dnmt1 gene and is suggestive of a role of DNMT1 in imprint resetting or maintenance in the male germ line. Key words: mouse, genomic imprinting, DNA methylation, DNMT1, DNMT3A, MTHFR. La methylation de l'ADN et les methyltransferases sont essentielles a la spermatogenese. Des mutations dans le gene de la methyltransferase Dnmt1 entrainent un effet paternel sur les etats epigenetiques et les phenotypes des descendants ce qui suggere que DNMT1 joue un role important dans la modification epigenetique du genome qui se produit au cours de la spermatogenese. Cependant, le role specifique de DNMT1 dans la spermatogenese et l'etablissement d'empreintes genomiques au sein des cellules germinales chez les males demeure inconnu. Afin de caracteriser plus avant l'effet d'une deficience en DNMT1 sur la reconfiguration des empreintes de methylation au cours de la spermatogenese, les auteurs ont analyse les profils de methylation des regions marquees chez les spermatozoides de souris heterozygotes pour une mutation complete (perte de fonction) de Dnmt1. La mutation n'a pas eu d'effet sur les regions H19 ou IG, normalement fortement methylees, mais a entraine une hypermethylation de la region Snrpn, une region qui est normalement non-methylee chez les spermatozoides matures. Ce phenotype n'est pas observe chez des souris ayant des mutations dans les genes Dnmt3a ou Mthfr, et serait ainsi specifique du gene Dnmt1; cela suggere un role de DNMT1 dans la reconfiguration des empreintes ou leur maintien au sein des cellules germinales chez les males. Mots-cles : souris, empreintes genomiques, methylation de l'ADN, DNMT1, DNMT3A, MTHFR. [Traduit par la Redaction], Introduction Genomic imprinting refers to a differential epigenetic marking of the genome during female and male gametogene sis that is preserved in the embryo after fertilization and persists over the [...]

An approach developed for mapping cis-regulatory variation based on interindividual variation in allelic expression (AE) is used to identify putative causal DNA variants that regulate long-range chromatin interactions. Studies on the regulation of asthma and autoimmune disease reveal that the genetic variants associated with them affect the expression of the ZPBP2/GSDMB/ORMDL3 gene locus in the chromosome 17q12-q21 region through allele-specific chromatin remodeling.

Transmission ratio distortion (TRD) is a deviation from the expected Mendelian 1:1 ratio of alleles transmitted from parents to offspring and may arise by different mechanisms. Earlier we described a grandparental-origin-dependent sex-of-offspring-specific TRD of maternal chromosome 12 alleles closely linked to an imprinted region and hypothesized that it resulted from imprint resetting errors in the maternal germline. Here, we report that the genotype of the parents for loss-of-function mutations in the Dnmt1 gene influences the transmission of grandparental chromosome 12 alleles. More specifically, maternal Dnmt1 mutations restore Mendelian transmission ratios of chromosome 12 alleles. Transmission of maternal alleles depends upon the presence of the Dnmt1 mutation in the mother rather than upon the Dnmt1 genotype of the offspring. Paternal transmission mirrors the maternal one: live-born offspring of wild-type fathers display 1:1 transmission ratios, whereas offspring of heterozygous Dnmt1 mutant fathers tend to inherit grandpaternal alleles. Analysis of allelic transmission in the homologous region of human chromosome 14q32 detected preferential transmission of alleles from the paternal grandfather to grandsons. Thus, parental Dnmt1 is a modifier of transmission of alleles at an unlinked chromosomal region and perhaps has a role in the genesis of TRD.

X-chromosome inactivation in carriers of Barth syndrome (BTHS), a rare X-linked recessive disorder involving myopathy of cardiac and skeletal muscles, small stature and neutropenia, is discussed. In 16 obligate carriers of BTHS from six families, PCR was used to analyze, and the skewed X inactivation in 11 of the 16 carriers likely comes from selection against cells with the mutated gene on the active X chromosome, but other factors probably influence expression of the phenotype, as BTHS shows much clinical variation in a family.

The present case report describes an Italian family with three affected probands, who exhibited serious mental disability, which has not been associated with other anomalies, except with slight facial dysmorphism. Molecular multigenic analysis for intellectual disability identified a previously unreported variant, p.Ile1765Met (c.5295C>G) in the SNF domain of the ATRX protein (in exon 24). The identified mutation was found in a hemizygous state in all three affected probands and in a heterozygous state in the asymptomatic mother and the female sibling. With respect to the phenotypic similarities found in the patients with those described in previous studies, the consistency in the mode of inheritance and segregation of the mutation, the variant reported in the present case report may be considered as ‘likely pathogenic’. To investigate the hypothesis that the preferential transmission of the ATRX mutation observed in this family reflected a general trend, a meta‑analysis into the segregation of ATRX mutations from published pedigrees, following allelic transmission from mothers who are heterozygous carriers to their offspring, was performed. A preferential transmission of the mutant allele to male offspring (58% of males inherited the mutant allele) was found; however, the bias was not statistically significant (P=0.29; χ² test). [ABSTRACT FROM AUTHOR]

The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR. [ABSTRACT FROM AUTHOR]

Background Two asthma-associated regions 17q12- q21 and 5q31.1 harbour genes that show strong effect of genotype on expression levels. DNA methylation has an important role in gene regulation; therefore, we examined DNA methylation at promoters of 12 genes from 5q31 and 17q12-q21 regions. Our goal was to determine whether DNA methylation was associated with predisposition to asthma and whether such a relationship was independent from genetic association. Methods Using sodium bisulfite sequencing and pyrosequencing methylation assays, we examined the effect of genotype on DNA methylation in peripheral blood cells from individuals from the Saguenay-Lac-Saint- Jean asthma familial collection and lymphoblastoid cell lines. Results The local genotype influenced methylation levels of solute carrier family 22 (organic 3 cation/ carnitine transporter) member 5 (SLC22A5), zona pellucida binding protein 2 (ZPBP2) and gasdermin A GSDMA) promoter regions. The genotype had a dominant effect on ZPBP2 and GSDMA methylation with lower methylation levels in individuals that carry the asthma-predisposing alleles. Males also had lower methylation at the ZPBP2 promoter than females. We did not observe an effect of asthma status that would be independent of the genotype and the sex effects in the GSDMA, ZPBP2 and SLC22A5 regions; however, GSDMA and ZPBP2 data were suggestive of interaction between asthma and methylation levels in females and SLC22A5 in males. Conclusions The local genotype influences methylation levels at SLC22A5 and ZPBP2 promoters independently of the asthma status. Further studies are necessary to confirm the relationship between GSDMA-ZPBP2 and SLC22A5 methylation and asthma in females and males separately. [ABSTRACT FROM AUTHOR]