Novel Role for a Sterol Response Element Binding Protein in Directing Spermatogenic Cell-Specific Gene Expression

Abstract

Sperm are highly specialized cells, and their formation requires the synthesis of a large number of unique mRNAs. However, little is known about the transcriptional mechanisms that direct male germ cell differentiation. Sterol response element binding protein 2gc (SREBP2gc) is a spermatogenic cell-enriched isoform of the ubiquitous transcription factor SREBP2, which in somatic cells is required for homeostatic regulation of cholesterol. SREBP2gc is selectively enriched in spermatocytes and spermatids, and, due to its novel structure, its synthesis is not subject to cholesterol feedback control. This suggested that SREBP2gc has unique cell-and stage-specific functions during spermatogenesis. Here, we demonstrate that this factor activates the promoter for the spermatogenesis-related gene proacrosin in a cell-specific manner. Multiple SREBP2gc response elements were identified within the 5-flanking and proximal promoter regions of the proacrosin promoter. Mutating these elements greatly diminished in vivo expression of this promoter in spermatogenic cells of transgenic mice. These studies define a totally new function for an SREBP as a transactivator of male germ cell-specific gene expression. We propose that SREBP2gc is part of a cadre of spermatogenic cell-enriched isoforms of ubiquitously expressed transcriptional coregulators that were specifically adapted in concert to direct differentiation of the male germ cell lineage.Sperm are highly differentiated cells that are uniquely adapted to their function as motile cells mediating fertilization. As such, they serve as an important model for exploring regulatory programs responsible for cellular differentiation (17). Spermatogenesis consists of a complex interplay between cellspecific gene transcription, RNA processing, and translational regulation (8,17). It occurs in a series of proliferation and differentiation stages, which can be subdivided into mitotic, meiotic, and spermiogenic phases. Each phase is characterized by distinct cell types, namely, spermatogonia, spermatocytes, and spermatids, respectively. The highly specialized nature of sperm is reflected in the large number of cell-specific transcripts and proteins they express (8), many of which are associated with unique sperm structures such as the acrosome, sperm tail, and the highly compacted sperm chromosomal DNA. Unique proteins also are required to meet specialized requirements for energy metabolism, meiosis, and the maturation of haploid cells, including cell-specific proteins that compensate for X chromosome inactivation (e.g., phosphoglycerate kinase 2 [pgk-2]) (9). These various gene products also must be expressed at the appropriate time to ensure normal development. Thus, sperm formation requires both the generation of a large number of cell-specific gene products and the coordination of this differentiation program in a stepwise, stage-appropriate manner. A key question is the nature of the transcriptional network that controls the elaboration of this program.Cell-specific transcription from ...

Basic mechanisms for the control of germ cell gene expression

“…A number of regulatory factors, including Sp1, NF-κB, CREMτ, BORIS, SREBP2, FIGα, and many others, have been proposed to regulate genes in germ cells (Lilienbaum et al, 2000;Loukinov et al, 2002;Foulkes et al, 1992;Thomas et al, 2005;Wang et al, 2004;reviewed in Eddy and O'Brien, 1998;Song and Wessel, 2005). Of the factors identified to date, the best characterized is CREMτ, an isoform of the cyclic AMP responsive activator CREM (Foulkes et al, 1992).…”

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: Intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage‐gated channels, methylation/acetylation, and transcription factors

“…SREBP2gc is a soluble constitutively active transcription factor that is not subjected to feedback control by sterols, possibly explaining the apparent sterol-insensitive expression of lipid synthesis genes during spermatogenesis (Wang et al, 2002). SREBP2gc is present in spermatocytes and spermatids and activates the promoter for the spermatogenesis-related gene acrosin (ACR) [ID: T2-207] in a cellspecific manner (Wang et al, 2004b). In addition to SREBP2gc, two other SREBP2 immunoreactive proteins (72 and 63 kDa) have been identified in the adult testis and both are insensitive to levels of cholesterol (Fon Tacer et al, 2003).…”

Computational identification of transcription frameworks of early committed spermatogenic cells

“…For example, it is likely that TFs work in concert as a transcription network to contextualize the expression of acrosin. Mutating the acrosin promoter SREBP2gc binding site was shown to decrease acrosin expression in spermatogenic cells (Wang et al 2004). In vitro experiments have also suggested several other co-regulatory TFs of acrosin, including Tet-1 and YY1 (Nayernia et al 1994; Schulten et al 1999, 2001).…”