Abstract
Previous studies on the epigenetic regulator DNA methyltransferase 3-Like (DNMT3L), have demonstrated it is an essential regulator of paternal imprinting and early male meiosis. Dnmt3L is also a paternal effect gene, i.e., wild type offspring of heterozygous mutant sires display abnormal phenotypes suggesting the inheritance of aberrant epigenetic marks on the paternal chromosomes. In order to reveal the mechanisms underlying these paternal effects, we have assessed X chromosome meiotic compaction, XY chromosome aneuploidy rates and global transcription in meiotic and haploid germ cells from male mice heterozygous for Dnmt3L. XY bodies from Dnmt3L heterozygous males were significantly longer than those from wild types, and were associated with a three-fold increase in XY bearing sperm. Loss of a Dnmt3L allele resulted in deregulated expression of a large number of both X-linked and autosomal genes within meiotic cells, but more prominently in haploid germ cells. Data demonstrate that similar to embryonic stem cells, DNMT3L is involved in an auto-regulatory loop in germ cells wherein the loss of a Dnmt3L allele resulted in increased transcription from the remaining wild type allele. In contrast, however, within round spermatids, this auto-regulatory loop incorporated the alternative non-coding alternative transcripts. Consistent with the mRNA data, we have localized DNMT3L within spermatids and sperm and shown that the loss of a Dnmt3L allele results in a decreased DNMT3L content within sperm. These data demonstrate previously unrecognised roles for DNMT3L in late meiosis and in the transcriptional regulation of meiotic and post-meiotic germ cells. These data provide a potential mechanism for some cases of human Klinefelter's and Turner's syndromes.
Highlights
Infertility affects 1 in 20 men in the Western world
The X and Y chromosomes form an XY body and become transcriptionally silent in a process known as meiotic sex chromosome inactivation (MSCI) [12,13]
Consistent with the Dnmt3L isoform data described above, the relative content of DNA methyltransferase 3-Like (DNMT3L) in sperm from Dnmt3L heterozygous males was reduced by 28% compared to sperm from wild type males (P = 0.027, n = 3 biological replicates with 2 mice per replicate) (Fig. 6C). These data show for the first time, that DNMT3L is a regulator of both XY body compaction and XY chromosomal segregation
Summary
Infertility affects 1 in 20 men in the Western world. Increasingly data is showing that in addition to genetic changes, aberrant epigenetic regulation during spermatogenesis can lead to human infertility [1,2,3]. Previous studies on the epigenetic regulator DNMT3L, have shown that deletion of Dnmt3L in mice resulted in hypomethylation of paternally imprinted regions and transposable elements in gonocytes, as well as developmental arrest and death of early meiotic cells [4,5,6]. Dnmt3L mRNA and protein were originally reported only in the primordial germ cells, where DNMT3L is needed to establish epigenetic marks required in early primary spermatocytes [4,7]. It was shown that Dnmt3L mRNA was present in spermatocytes and spermatids [5,8]. It was shown that a second promoter in intron 9 initiates three alternative transcripts (Forms 1, 2 and 3) in late pachytene spermatocytes and round spermatids [9]. The localization of DNMT3L protein within the adult testis or sperm has not been reported
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
