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

Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue N, Worcester, MA 01655-0127. USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2005; 24(24):10681-8. DOI: 10.1128/MCB.24.24.10681-10688.2004
Source: PubMed


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.

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Available from: Daniel L Kilpatrick, Jul 25, 2014
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    • "Four members of the SREBP family, SREBP-1a, SREBP-1c, SREBP-2 and SREBP-2gc, have been identified [2-5]. SREBPs are a family of transcription factors that have independently been characterized as mediators of cellular cholesterol homeostasis [6,7] and as regulators of fatty acid biosynthesis and uptake [8-10]. "
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    ABSTRACT: The molecular mechanism of how cells maintain cholesterol homeostasis has become clearer for the understanding of complicated association between sterol regulatory element-binding proteins (SREBPs), SREBP cleavage-activating protein (SCAP), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and Insuin induced-genes (Insigs). The pioneering researches suggested that SREBP activated the transcription of genes encoding HMG-CoA reductase and all of the other enzymes involved in the synthesis of cholesterol and lipids. However, SREBPs can not exert their activities alone, they must form a complex with another protein, SCAP in the endoplasmic reticulum (ER) and translocate to Golgi. Insigs are sensors and mediators that regulate cholesterol homeostasis through binding to SCAP and HMG-CoA reductase in diverse tissues such as adipose tissue and liver, as well as the cultured cells. In this article, we aim to review on the dual functions of Insig protein family in cholesterol homeostasis.
    Full-text · Article · Dec 2012 · Lipids in Health and Disease
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    • "In testing the system, we noted the presence of the YY1 response element in the upstream regions of all three genes in the protamine domain that has been associated with a sterol response element binding protein that regulates proacrosin, another haploid expressed gene. [39]. The developmentally significant GATA family of elements were also over-represented in biologically significant locations in two of the three genes. "
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    ABSTRACT: Understanding the regulatory processes that coordinate the cascade of gene expression leading to male gamete development has proven challenging. Research has been hindered in part by an incomplete picture of the regulatory elements that are both characteristic of and distinctive to the broad population of spermatogenically expressed genes. K-SPMM, a database of murine Spermatogenic Promoters Modules and Motifs, has been developed as a web-based resource for the comparative analysis of promoter regions and their constituent elements in developing male germ cells. The system contains data on 7,551 genes and 11,715 putative promoter regions in Sertoli cells, spermatogonia, spermatocytes and spermatids. K-SPMM provides a detailed portrait of promoter site components, ranging from broad distributions of transcription factor binding sites to graphical illustrations of dimeric modules with respect to individual transcription start sites. Binding sites are identified through their similarities to position weight matrices catalogued in either the JASPAR or the TRANSFAC transcription factor archives. A flexible search function allows sub-populations of promoters to be identified on the basis of their presence in any of the four cell-types, their association with a list of genes or their component transcription-factor families. This system can now be used independently or in conjunction with other databases of gene expression as a powerful aid to research networks of co-regulation. We illustrate this with respect to the spermiogenically active protamine locus in which binding sites are predicted that align well with biologically foot-printed protein binding domains.
    Full-text · Article · Feb 2006 · BMC Bioinformatics
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    • "The post-meiotic transcription of genes raises the possibility of the specific expression of X or Y chromosomal genes localised in round spermatids and cytoplasmic fragments (Hendrikson et al. 1995). Among the candidate genes that have been implicated in testicular post-meiotic germ cell development are Xist, CREMtau, p63, SREBP2 gc and extra-embryonic tissue-spermatogenesis-homeobox gene 1 (Esx1, also known as Spx1; Dolci et al. 1994; Poulat et al. 1995; Li et al. 1997; Li and Behringer 1998; Nakamuta and Kobayashi 2004; Wang et al. 2004). To examine the possibility of these gene products being used as markers for X chromosome-bearing sperm, we investigated Esx1. "
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    ABSTRACT: Extra-embryonic tissue-spermatogenesis-homeobox gene 1 (Esx1) encodes an X-linked homeobox protein. Despite the fact that the temporal and spatial mRNA expression pattern of the protein has been studied extensively in the testis, specific localisation of ESX1 in the testis remains to be determined. In the present study, we generated ESX1 antiserum to investigate the stage- and tissue-specific expression of ESX1 in the mouse. Western blotting and immunofluorescent analyses revealed that general localisations of ESX1 were consistent with its RNA expression patterns; that is, it was restricted mainly to the placenta and testis. Immunofluorescent studies demonstrated that ESX1 existed in the testes after 3 weeks of age, coincident with the appearance of round spermatids in the seminiferous tubules. Moreover, ESX1 expression became more abundant in the luminal regions of the seminiferous tubules as the development of round spermatids progressed into spermatozoa. In contrast, reduced expression of ESX1 was observed in experimentally induced cryptorchid testes. The later expression of ESX1 suggests a role in post-meiotic germ cell development. To further understand ESX1 expression in sperm with respect to X chromosome-bearing sperm, we used ESX1 antiserum to immunostain sperm by confocal laser microscopy. Approximately half the sperm population was recognised by the ESX1 antiserum. On the basis of results of the present study, we suggest that ESX1 could be used as a protein marker for X chromosome-bearing sperm.
    Preview · Article · Feb 2005 · Reproduction Fertility and Development
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