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To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo.
© 2014 Ihara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ihara, M., Meyer-Ficca, M. L., Leu, N. A., Rao, S., Li, F., Gregory, B. D., Zalenskaya, I. A., Schultz, R. M., & Meyer, R. G. (2014). Paternal Poly (ADP-ribose) Metabolism Modulates Retention of Inheritable Sperm Histones and Early Embryonic Gene Expression. PLoS Genetics, 10 (5), http://dx.doi.org/10.1371/journal.pgen.1004317
Additional FilesFigure 1_Paternal Poly (ADP-ribose) Metabolism.pdf (137 kB)
Figure 2_Paternal Poly (ADP-ribose) Metabolism.pdf (238 kB)
Table 1_Paternal Poly (ADP-ribose) Metabolism.pdf (460 kB)
Figure 3_Paternal Poly (ADP-ribose) Metabolism.pdf (213 kB)
Figure 4_Paternal Poly (ADP-ribose) Metabolism.pdf (247 kB)
Table 2_Paternal Poly (ADP-ribose) Metabolism.pdf (272 kB)
Figure 5_Paternal Poly (ADP-ribose) Metabolism.pdf (249 kB)
Figure 6_Paternal Poly (ADP-ribose) Metabolism.pdf (230 kB)
Figure 7_Paternal Poly (ADP-ribose) Metabolism.pdf (199 kB)
Date Posted:11 July 2017
This document has been peer reviewed.