Male-specific transcription initiation of the C4-Slp gene in mouse liver follows activation of STAT5.
The mouse genes encoding the constitutively expressed complement component C4 and its closely related isoform C4-Slp (sex-limited protein), which is expressed only in male animals of several strains, provide a unique model to study sequence elements and trans-acting factors responsible for androgen responsiveness. Our previous studies have shown that hormonal induction of C4-Slp is mediated by a sex-specific pattern of growth hormone secretion. Promoter analyses in vitro have led to contradictory conclusions concerning the significance of C4-Slp-specific sequences in the 5' flanking region. Mutant mice carrying the H-2(aw18) haplotype, which is characterized by a large deletion in the S region covering the C4 and 21-OHase A genes, permit the direct in vivo analysis of C4-Slp transcription, unhindered by the presence of C4. Run-on analysis of transcription in liver nuclei of males and females of this strain demonstrated a 100-fold higher transcriptional activity in males, essentially determined at the transcription initiation level. The androgen dependence of transcription initiation was confirmed by run-on analysis of testosterone-treated females, where transcriptional activity started after 6 days of androgen treatment and reached male levels after 20 days. Conversely, the growth hormone-regulated activity of transcription factor STAT5 was already detected in liver nuclei after 48 hr of androgen treatment. Furthermore, we demonstrate that activated STAT5 recognizes in vitro two upstream gamma interferon-activated sequence (GAS) elements of the C4-Slp gene, centered at positions -1969 and -1831. We postulate that binding of STAT5 to these C4-Slp-specific GAS elements plays a crucial role in the chromatin remodelings that lead to transcriptional competence of the C4-Slp gene in the liver.
Unité d'Immunogénétique et Institut National de la Santé et de la Recherche Médicale, U. 276, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
N
N
Varin-Blank
E
E
Dondi
M
M
Tosi
C
C
Hernandez
L
L
Boucontet
H
H
Gotoh
T
T
Shiroishi
K
K
Moriwaki
T
T
Meo
D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics*; D003181:Complement C4 / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D012727:Sex Characteristics; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D001798:Blood Proteins; C018386:C4a protein, mouse; D003181:Complement C4; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D013006:Growth Hormone