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An analysis of nucleoside active metabolite potencies against Hepatitis C virus (HCV) versus their parent ground-state energetic conformational bias as calculated by density functional theory suggested that nucleotides with a small difference between their antipodal energies are more likely to have potent antiviral activity compared to those with larger energetic differences. This energetic conformational bias was thought to be manipulated with substitutions along the ­ribofuranose ring. From 2′-C-methyluridine, a representative nucleoside with fair anti-HCV activity, two C3′ modifications in particular (ethyne and methyl) showed contrasting antipodal biases relative to each other while originating from a common synthetic intermediate, allowing a test of reasonable extremes of the computational model with a divergent nine-step synthesis. Antiviral activity of the compounds contradicted that suggested by the model, indicating a need for further refinement with additional biostructural considerations.

The epigenetic information present in mammalian gametes and whether it is transmitted to the progeny are relatively unknown. We find that many promoters in mouse sperm are occupied by RNA polymerase II (Pol II) and Mediator. The same promoters are accessible in GV and MII oocytes and preimplantation embryos. Sperm distal ATAC-seq sites containing motifs for various transcription factors are conserved in monkeys and humans. ChIP-seq analyses confirm that Foxa1, ERα, and AR occupy distal enhancers in sperm. Accessible sperm enhancers containing H3.3 and H2A.Z are also accessible in oocytes and preimplantation embryos. Furthermore, their interactions with promoters in the gametes persist during early development. Sperm- or oocyte-specific interactions mediated by CTCF and cohesin are only present in the paternal or maternal chromosomes, respectively, in the zygote and 2-cell stages. These interactions converge in both chromosomes by the 8-cell stage. Thus, mammalian gametes contain complex patterns of 3D interactions that can be transmitted to the zygote after fertilization.

Transgenerational inheritance requires mechanisms by which epigenetic information is transferred via gametes. Canonical thought holds that mammalian sperm chromatin would be incapable of carrying epigenetic information as post-translational modifications of histones because of their replacement with protamine proteins. Furthermore, compaction of the sperm genome would hinder DNA accessibility of proteins involved in transcriptional regulation and genome architecture. In this Minireview, we delineate the paternal chromatin remodeling events during spermatogenesis and fertilization. Sperm chromatin is epigenetically modified at various time points throughout its development. This allows for the addition of environment-specific modifications that can be passed from parents to offspring.