Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development

Sandra Yassine, Jessica Escoffier, Guillaume Martinez, Charles Coutton, Thomas Karaouzéne, Raoudha Zouari, Jean Luc Ravanat, Catherine Metzler-Guillemain, Hoi Chang Lee, Rafael Fissore, Sylviane Hennebicq, Pierre F. Ray, Christophe Arnoult*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

We recently identified the DPY19L2 gene as the main genetic cause of human globozoospermia. Non-genetically characterized cases of globozoospermia were associated withDNAalterations, suggesting that DPY19L2-dependent globozoospermia maybe associated with poor DNA quality. However the origins of such defects have not yet been characterized and the consequences on the quality of embryos generated with globozoospermic sperm remain to be determined. Using themousemodel lacking Dpy19l2,wecomparedseveral key steps of nuclear compaction. We show that the kinetics of appearance and disappearance of the histone H4 acetylation waves and of transition proteins are defective. More importantly, the nuclear invasion by protamines does not occur. As a consequence, we showed that globozoospermic sperm presented with poor sperm chromatin compaction and sperm DNA integrity breakdown. We next assessed the developmental consequences of using such faulty sperm by performing ICSI. We showedin the companion article that oocyte activation (OA) with globozoospermic sperm is very poor and due to the absence of phospholipase Cz; therefore artificial OA (AOA) was used to bypass defective OA. Herein, we evaluated the developmental potential of embryos generated by ICSI + AOA in mice. We demonstrate that although OAwas fully rescued, preimplantation development was impaired when using globozoospermic sperm. In human, a small number of embryos could be generated with sperm from DPY19L2-deleted patients in the absence of AOA and these embryos also showed a poor developmental potential. In conclusion, we show that chromatin compaction during spermiogenesis in Dpy19l2 KO mouse is defective and leads to sperm DNA damage. Most of the DNA breaks were already present when the sperm reached the epididymis, indicating that they occurred inside the testis. This result thus suggests that testicular sperm extraction in Dpy1 9l2-dependent globozoospermia is not recommended. These defects may largely explain the poor embryonic development of most mouse and human embryos obtained with globozoospermic sperm.

Original languageEnglish (US)
Article numbergau099
Pages (from-to)169-185
Number of pages17
JournalMolecular human reproduction
Volume21
Issue number2
DOIs
StatePublished - Aug 27 2014
Externally publishedYes

Keywords

  • DNA compaction
  • Dpy1 9l2
  • Globozoospermia
  • Male infertility
  • Protamine

ASJC Scopus subject areas

  • Reproductive Medicine
  • Embryology
  • Molecular Biology
  • Genetics
  • Obstetrics and Gynecology
  • Developmental Biology
  • Cell Biology

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