KDM1A/LSD1 regulates the differentiation and maintenance of spermatogonia in mice

Abstract

The proper regulation of spermatogenesis is crucial to ensure the continued production of sperm and fertility. Here, we investigated the function of the H3K4me2 demethylase KDM1A/LSD1 during spermatogenesis in developing and adult mice. Conditional deletion of Kdm1a in the testis just prior to birth leads to fewer spermatogonia and germ cell loss before 3 weeks of age. These results demonstrate that KDM1A is required for spermatogonial differentiation, as well as germ cell survival, in the developing testis. In addition, inducible deletion of Kdm1a in the adult testis results in the abnormal accumulation of meiotic spermatocytes, as well as apoptosis and progressive germ cell loss. These results demonstrate that KDM1A is also required during adult spermatogenesis. Furthermore, without KDM1A, the stem cell factor OCT4 is ectopically maintained in differentiating germ cells. This requirement for KDM1A is similar to what has been observed in other stem cell populations, suggesting a common function. Taken together, we propose that KDM1A is a key regulator of spermatogenesis and germ cell maintenance in the mouse.

Dopamine Receptor D1 Contributes to Cocaine Epigenetic Reprogramming of Histone Modifications in Male Germ Cells

“…KMT1C/G9A is a key mediator of the epigenetic effects of cocaine in the mesolimbic system (Maze et al, 2010;Anderson et al, 2019) and has been described as a crucial epigenetic marker of heterochromatin formation during meiosis (Tachibana et al, 2007). KDM1A/LSD1 participates in the demethylation of H3K4/K9 and is required for spermatogonial differentiation and germ cell survival in mice (Myrick et al, 2017). Also, it has been found that many bivalent genes have increased H3K4me3 and decreased H3K27me3 levels and are occupied by KDM1A/LSD1 to maintain low levels of H3K4me2 that often co-localized with H3K4me3 (Adamo et al, 2011;Whyte et al, 2012).…”

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

“…The KDM1A has been shown to directly bind OCT4 gene in a mouse germ cell line (GC-1 cells) and remove H3K4me2 at the Accumulating evidence considers H3K4me2 in the maintenance of transcriptional active states. Interestingly, conditional deletion of KDM1A, a H3K4me2 demethylase, induces a severe effect on differentiation of SPG and a complete loss of germ cells [22,109]. Remarkably, KDM1A loss is associated with a profound alteration of gene expression including those that are essential to undifferentiated SPG maintenance (i.e., PLZF, NANOS2 and BCL6b) [109].…”

“…The KDM1A has been shown to directly bind OCT4 gene in a mouse germ cell line (GC-1 cells) and remove H3K4me2 at the promoter and proximal enhancers. This allows transcriptional repression of OCT4, favoring SPG commitment and differentiation [22] ( Figure 3A,B).…”

Molecular regulation of spermatogonial stem cell renewal and differentiation

“…This system would ensure that a Box 2: Epigenetic regulation of A undiff KDM1A (lysine (K)-specific demethylase 1A) is a histone H3 lysine demethylase with gene-regulating activities including but not limited to removal of mono-and di-methylation at lysine 4 on histone H3 (H3K4). KDM1A is needed for postnatal maintenance of the germline, and its loss results in rapid depletion of all germ cells potentially due to destabilization of gene expression and the consequent inability to maintain functional SSCs or the spermatogenic process (Lambrot et al 2015, Myrick et al 2017. However, available data do not allow definitive conclusions to be drawn and further studies are needed to elucidate the functional role of KDM1A in A undiff .…”