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PLoS Genet. 2014 May 8;10(5):e1004317. doi: 10.1371/journal.pgen.1004317. eCollection 2014 May.

Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression.

Author information

1
Department of Animal Biology and Center for Animal Transgenesis and Germ Cell Research, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
2
Department of Animal Biology and Center for Animal Transgenesis and Germ Cell Research, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
3
School of Medicine, Microarray Core Facility, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
4
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; School of Arts and Sciences, Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
5
CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
6
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Abstract

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.

PMID:
24810616
PMCID:
PMC4014456
DOI:
10.1371/journal.pgen.1004317
[Indexed for MEDLINE]
Free PMC Article
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