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Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development.
Mol Hum Reprod. 2015 Feb; 21(2):169-85.MH

Abstract

We recently identified the DPY19L2 gene as the main genetic cause of human globozoospermia. Non-genetically characterized cases of globozoospermia were associated with DNA alterations, suggesting that DPY19L2-dependent globozoospermia may be 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 the mouse model lacking Dpy19l2, we compared several 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 showed in the companion article that oocyte activation (OA) with globozoospermic sperm is very poor and due to the absence of phospholipase Cζ; 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 OA was 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 Dpy19l2-dependent globozoospermia is not recommended. These defects may largely explain the poor embryonic development of most mouse and human embryos obtained with globozoospermic sperm.

Authors+Show Affiliations

Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France CHU de Grenoble, UF de Génétique Chromosomique, Grenoble, F-38000, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France.Clinique des Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisia.Université Grenoble Alpes, Grenoble, F-38000, France Laboratoire Lésions des Acides Nucléiques, CEA, INAC-SCIB, F-38000 Grenoble, France.Aix-Marseille Université-Inserm UMR 910, Génétique médicale et Génomique Fonctionnelle, 13385 Marseille Cedex 5, France APHM Hôpital La Conception, Gynépôle, Laboratoire de Biologie de la Reproduction - CECOS, 13385 Marseille Cedex 5, France.Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, 661 North Pleasant Street, Amherst, MA 01003, USA.Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, 661 North Pleasant Street, Amherst, MA 01003, USA.Université Grenoble Alpes, Grenoble, F-38000, France CHU de Grenoble, Centre d'AMP-CECOS, BP217, Grenoble Cedex 9, F-38043, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France CHU de Grenoble, UF de Biochimie et Génétique Moléculaire, Grenoble, F-38000, France.Université Grenoble Alpes, Grenoble, F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche, F-38700, France christophe.arnoult@ujf-grenoble.fr.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25354700

Citation

Yassine, Sandra, et al. "Dpy19l2-deficient Globozoospermic Sperm Display Altered Genome Packaging and DNA Damage That Compromises the Initiation of Embryo Development." Molecular Human Reproduction, vol. 21, no. 2, 2015, pp. 169-85.
Yassine S, Escoffier J, Martinez G, et al. Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development. Mol Hum Reprod. 2015;21(2):169-85.
Yassine, S., Escoffier, J., Martinez, G., Coutton, C., Karaouzène, T., Zouari, R., Ravanat, J. L., Metzler-Guillemain, C., Lee, H. C., Fissore, R., Hennebicq, S., Ray, P. F., & Arnoult, C. (2015). Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development. Molecular Human Reproduction, 21(2), 169-85. https://doi.org/10.1093/molehr/gau099
Yassine S, et al. Dpy19l2-deficient Globozoospermic Sperm Display Altered Genome Packaging and DNA Damage That Compromises the Initiation of Embryo Development. Mol Hum Reprod. 2015;21(2):169-85. PubMed PMID: 25354700.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development. AU - Yassine,Sandra, AU - Escoffier,Jessica, AU - Martinez,Guillaume, AU - Coutton,Charles, AU - Karaouzène,Thomas, AU - Zouari,Raoudha, AU - Ravanat,Jean-Luc, AU - Metzler-Guillemain,Catherine, AU - Lee,Hoi Chang, AU - Fissore,Rafael, AU - Hennebicq,Sylviane, AU - Ray,Pierre F, AU - Arnoult,Christophe, Y1 - 2014/10/29/ PY - 2014/10/31/entrez PY - 2014/10/31/pubmed PY - 2015/10/20/medline KW - DNA compaction KW - Dpy19l2 KW - globozoospermia KW - male infertility KW - protamine SP - 169 EP - 85 JF - Molecular human reproduction JO - Mol. Hum. Reprod. VL - 21 IS - 2 N2 - We recently identified the DPY19L2 gene as the main genetic cause of human globozoospermia. Non-genetically characterized cases of globozoospermia were associated with DNA alterations, suggesting that DPY19L2-dependent globozoospermia may be 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 the mouse model lacking Dpy19l2, we compared several 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 showed in the companion article that oocyte activation (OA) with globozoospermic sperm is very poor and due to the absence of phospholipase Cζ; 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 OA was 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 Dpy19l2-dependent globozoospermia is not recommended. These defects may largely explain the poor embryonic development of most mouse and human embryos obtained with globozoospermic sperm. SN - 1460-2407 UR - https://www.unboundmedicine.com/medline/citation/25354700/Dpy19l2_deficient_globozoospermic_sperm_display_altered_genome_packaging_and_DNA_damage_that_compromises_the_initiation_of_embryo_development_ L2 - https://academic.oup.com/molehr/article-lookup/doi/10.1093/molehr/gau099 DB - PRIME DP - Unbound Medicine ER -