To better understand transcriptional regulation during human oogenesis and pre-implantation development, we defined stage-specific transcription, which revealed the cleavage stage as highly distinctive. Here, we present multiple lines of evidence that a eutherian-specific, multi-copy retrogene, DUX4, encodes a transcription factor which activates hundreds of endogenous genes (e.g. ZSCAN4, ZFP352, KDM4E) and retroviral elements (MERVL/HERVL-family) that defines the cleavage-specific transcriptional programs in mouse and human. Remarkably, mouse Dux expression is both necessary and sufficient to convert mouse embryonic stem cells into two-cell embryo-like (‘2C-like’) cells, measured here by the reactivation of ‘2C’ genes and repeat elements, the loss of POU5F1 protein and chromocenters, and by the conversion of the chromatin landscape (assessed by ATAC-seq) to a state strongly resembling mouse two-cell embryos. Taken together, we propose mouse DUX and human DUX4 as major drivers of the cleavage/‘2C’ state.

Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9–19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.

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