mouse Archives - Episona
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Disruption of histone methylation in developing sperm impairs offspring health transgenerationally
Nov 2015 - Science
Keith Siklenka, Serap Erkek, Maren Godmann, Romain Lambrot, Serge McGraw, Christine Lafleur, Tamara Cohen, Jianguo Xia, Matthew Suderman, Michael Hallett, Jacquetta Trasler, Antoine H. F. M. Peters, Sarah Kimmins
A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown. <!--more-->We generated transgenic mice in which overexpression of the histone H3 lysine 4 (H3K4) demethylase KDM1A (also known as LSD1) during spermatogenesis reduced H3K4 dimethylation in sperm. KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects persisted transgenerationally in the absence of KDM1A germline expression and were associated with altered RNA profiles in sperm and offspring. We show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.
Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis
Oct 2015 - Biochem J
Maria B. Garcia-Fabiani, Mauro A. Montanaro, Ezequiel Lacunza, Elizabeth R. Cattaneo, Rosalind A. Coleman, Magali Pellon-Maison, Maria R. Gonzalez-Baro
Spermatogenesis is a highly regulated process that involves both mitotic and meiotic divisions, as well as cellular differentiation to yield mature spermatozoa from undifferentiated germinal stem cells. Although Gpat2 was originally annotated as encoding a glycerol-3-phosphate acyltransferase by sequence homology to Gpat1, GPAT2 is highly expressed in testis but not in lipogenic tissues and is not up-regulated during adipocyte differentiation. New data show that GPAT2 is required for the synthesis of piRNAs (piwi-interacting RNAs), a group of small RNAs that protect the germ cell genome from retrotransposable elements. <!--more-->In order to understand the relationship between GPAT2 and its role in the testis, we focused on Gpat2 expression during the first wave of mouse spermatogenesis. Gpat2 expression was analysed by qPCR (quantitative real-time PCR), in situ hybridization, immunohistochemistry and Western blotting. Gpat2 mRNA content and protein expression were maximal at 15 dpp (days post-partum) and were restricted to pachytene spermatocytes. To achieve this transient expression, both epigenetic mechanisms and trans-acting factors are involved. In vitro assays showed that Gpat2 expression correlates with DNA demethylation and histone acetylation and that it is up-regulated by retinoic acid. Epigenetic regulation by DNA methylation was confirmed in vivo in germ cells by bisulfite sequencing of the Gpat2 promoter. Consistent with the initiation of meiosis at 11 dpp, methylation decreased dramatically. Thus, Gpat2 is expressed at a specific stage of spermatogenesis, consistent with piRNA synthesis and meiosis I prophase, and its on–off expression pattern responds predominantly to epigenetic modifications.
Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility
Jul 2013 - PNAS
Bedrich Mosinger, Kevin M. Redding, M. Rockwell Parker, Valeriya Yevshayeva, Karen K. Yee, Katerina Dyomina, Yan Li, Robert F. Margolskee
TAS1R taste receptors and their associated heterotrimeric G protein gustducin are involved in sugar and amino acid sensing in taste cells and in the gastrointestinal tract. They are also strongly expressed in testis and sperm, but their functions in these tissues were previously unknown. Using mouse models, we show that the genetic absence of both TAS1R3, a component of sweet and amino acid taste receptors, and the gustducin α-subunit GNAT3 leads to male-specific sterility. <!--more-->To gain further insight into this effect, we generated a mouse model that expressed a humanized form of TAS1R3 susceptible to inhibition by the antilipid medication clofibrate. Sperm formation in animals without functional TAS1R3 and GNAT3 is compromised, with malformed and immotile sperm. Furthermore, clofibrate inhibition of humanized TAS1R3 in the genetic background of Tas1r3−/−, Gnat3−/− doubly null mice led to inducible male sterility. These results indicate a crucial role for these extraoral “taste” molecules in sperm development and maturation. We previously reported that blocking of human TAS1R3, but not mouse TAS1R3, can be achieved by common medications or chemicals in the environment. We hypothesize that even low levels of these compounds can lower sperm count and negatively affect human male fertility, which common mouse toxicology assays would not reveal. Conversely, we speculate that TAS1R3 and GNAT3 activators may help infertile men, particularly those that are affected by some of the mentioned inhibitors and/or are diagnosed with idiopathic infertility involving signaling pathway of these receptors.
Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice
Oct 2015 - FASEB J
Alexander K. Murashov, Elena S. Pak, Michael Koury, Ajay Ajmera, Maneesh Jeyakumar, Matthew Parker, Oksana Williams, Jian Ding, Dianne Walters, P. Darrell Neufer
Obesity has more than doubled in children and tripled in adolescents in the past 30 yr. The association between metabolic disorders in offspring of obese mothers with diabetes has long been known; however, a growing body of research indicates that fathers play a significant role through presently unknown mechanisms. Recent observations have shown that changes in paternal diet may result in transgenerational inheritance of the insulin-resistant phenotype. <!--more-->Although diet-induced epigenetic reprogramming via paternal lineage has recently received much attention in the literature, the effect of paternal physical activity on offspring metabolism has not been adequately addressed. In the current study, we investigated the effects of long-term voluntary wheel-running in C57BL/6J male mice on their offspring's predisposition to insulin resistance. Our observations revealed that fathers subjected to wheel-running for 12 wk produced offspring that were more susceptible to the adverse effects of a high-fat diet, manifested in increased body weight and adiposity, impaired glucose tolerance, and elevated insulin levels. Long-term paternal exercise also altered expression of several metabolic genes, including Ogt, Oga, Pdk4, H19, Glut4, and Ptpn1, in offspring skeletal muscle. Finally, prolonged exercise affected gene methylation patterns and micro-RNA content in the sperm of fathers, providing a potential mechanism for the transgenerational inheritance. These findings suggest that paternal exercise produces offspring with a thrifty phenotype, potentially via miRNA-induced modification of sperm.
The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine
Oct 2015 - BMC Genomics
Aurore Gely-Pernot, Chunxiang Hao, Emmanuelle Becker, Igor Stuparevic, Christine Kervarrec, Frédéric Chalmel, Michael Primig, Bernard Jégou, Fatima Smagulova
Environmental factors such as pesticides can cause phenotypic changes in various organisms, including mammals. We studied the effects of the widely used herbicide atrazine (ATZ) on meiosis, a key step of gametogenesis, in male mice. Gene expression pattern was analysed by Gene-Chip array. <!--more-->Genome-wide mapping of H3K4me3 marks distribution was done by ChIP-sequencing of testis tissue using Illumina technologies. RT-qPCR was used to validate differentially expressed genes or differential peaks. We demonstrate that exposure to ATZ reduces testosterone levels and the number of spermatozoa in the epididymis and delays meiosis. Using Gene-Chip and ChIP-Seq analysis of H3K4me3 marks, we found that a broad range of cellular functions, including GTPase activity, mitochondrial function and steroid-hormone metabolism, are affected by ATZ. Furthermore, treated mice display enriched histone H3K4me3 marks in regions of strong recombination (double-strand break sites), within very large genes and reduced marks in the pseudoautosomal region of X chromosome. Our data demonstrate that atrazine exposure interferes with normal meiosis, which affects spermatozoa production.