Sperm chromatin: fertile grounds for proteomic discovery of clinical tools

Abstract

Sperm are remarkably complex cells with a singularly important mission: to deliver paternal DNA and its associated factors to the oocyte to start a new life. The integrity of sperm DNA is a keystone of reproductive success, which includes fertilization and embryonic development. In addition, the significance in these processes of proteins that associate with sperm DNA is increasingly being appreciated. In this review, we highlight proteomic studies that have identified sperm chromatin proteins with fertility roles that have been validated by molecular studies in model organisms or correlations in the clinic. Up to 50% of male-factor infertility cases in the clinic have no known cause and therefore no direct treatment. In-depth study of the molecular basis of infertility has great potential to inform the development of sensitive diagnostic tools and effective therapies that will address this incongruity. Because sperm rely on testis-specific protein isoforms and post-translational modifications for their development and function, sperm-specific processes are ideal for proteomic explorations that can bridge the research lab and fertility clinic.

Fig. 1.

Human sperm and sperm development. A, schematic of a human sperm cell, which is composed of three regions. The head region contains the highly compacted sperm DNA and associated proteins (blue) surrounded by the cellular membrane (black) that in the head region have receptors for recognizing oocyte factors. The acrosome (purple) houses digestive enzymes used for penetrating the oocyte outer layers. The mid-piece region consists of the paternally contributed centrosome (green circle) and mitochondria (tan) used for energy generation. The flagellar tail (green) provides motility. B, diagram of testis, epididymis, and vas deferens. Sperm develop within the seminiferous tubules that are coiled within the testis. Sperm transit to the epididymis where they further mature and are then stored in the vas deferens. Contraction of the vas deferens propels sperm through the male reproductive tract during ejaculation. Image from LifeART (and/or) MediClip® (2008) Wolters Kluwer Health, Inc.- Lippincott Williams & Wilkins. All rights reserved. C, diagram of human sperm formation and associated processes. A cross-section of a seminiferous tubule found within the testis is illustrated. Germinal stem cells renew through repeated rounds of mitosis then shift to meiosis to form primary and secondary spermatocytes. After meiosis, haploid cells undergo spermiogenesis, where DNA is tightly compacted, and transcription is largely silenced. Cells also differentiate morphologically to form flagella. In the epididymis, sperm mature to become motile, and cellular membranes are prepared for fertilization. After transfer to the female reproductive tract, sperm cellular membranes undergo further changes, and sperm become highly motile, a process known as capacitation. Upon binding with the oocyte, acrosomes release enzymes to penetrate oocyte outer layers to allow sperm-egg membrane fusion for fertilization.