Epigenetic changes in mammalian gametes throughout their lifetime: the four seasons metaphor

The ability to reproduce is a major trait of living organisms. This ability is carried out by specialized reproductive cells-gametes. In mammals, gametes develop through a unique developmental pathway. Extensive changes in the epigenome of gametes occur during embryonic development. With birth, gametes continue to mature and develop until puberty. This growth process is accompanied by further epigenetic changes. When gametes mature, they reside within specialized organs-the gonads-and are exposed to both internal and external signals. The gametes' epigenome reacts to these signals, and epigenetic changes which occur can alter gene expression and the ability of the cells to go through the cell cycle. The epigenome also ages and may be one of the key players in gamete aging, which, at least for females, occurs relatively early in life. The journey gametes undertake throughout the life of the organism is thus full of epigenetic changes. In this review, we depict these changes and the mechanisms involved in them. We focus on four stages of gamete development: gametes in embryonic development, during puberty and until sexual maturity, in adulthood, and during the process of aging. In each stage, we focus on one aspect of epigenetic changes and discuss it in more detail. These four stages include many different molecular players, lots of enzymatic activity, and abrupt changes. By this, these stages resemble the four seasons of the year. Thus, we describe epigenetic changes in gametes as changes throughout four seasons of life.