Novel role for a sterol response element binding protein in directing spermatogenic cell-specific gene expression.
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.
Wang
Hang
H
Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue N, Worcester, MA 01655-0127. USA.
San Agustin
Jovenal T
JT
Witman
George B
GB
Kilpatrick
Daniel L
DL
D041721:3T3-L1 Cells; D024506:5' Flanking Region; D000176:Acrosin / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004792:Enzyme Precursors / Q000235:genetics; D015870:Gene Expression; D018257:Helix-Loop-Helix Motifs; D016350:Leucine Zippers; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009154:Mutation; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics / Q000502:physiology*; D013087:Spermatids / Q000737:chemistry / Q000378:metabolism; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000737:chemistry / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D020033:Protein Isoforms; D012333:RNA, Messenger; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D015534:Trans-Activators; D014157:Transcription Factors; D008156:Luciferases; C022438:proacrosin; D000176:Acrosin