A novel two-promoter-one-gene system of the chorionic gonadotropin β gene enables tissue-specific expression

Abstract

The New World monkey (NWM), Callithrix jacchus, a preferred model in medical research, displays an interesting endocrine regulation of reproduction: LH, the heterodimeric glycoprotein hormone, is functionally replaced by the chorionic gonadotropin (CG), a hormone indispensable for establishment of pregnancy in humans and normally expressed in the placenta. In the marmoset pituitary, the expression of the b-subunit (CGB) gene is regulated similar to human LH b-subunit, but its placental regulation is unknown. This study intended to decipher the underlying mechanism of tissue-specific expression of CGB in the marmoset placenta. We identified a new placental transcriptional start site, described a new, previously undiscovered exon, and define a novel placental core promoter in the marmoset CGB gene. This promoter contains a TATA box and binding sites for activating protein 2 and selective promoter factor 1, the latter acting synergistically by forming a regulation cassette. Differential first exon usage directed the tissue-specific expression. Methylation analyses revealed a tissue-specific pattern in the placental promoter indicating additional epigenetic regulation of gene expression. Our findings point toward a hitherto unknown evolutionary plasticity in the LH/CG hormonal system in NWM, which could be used as a model to study human CGB regulation in clinical pathologies.

Regulation of human chorionic gonadotropin beta subunit expression in ovarian cancer

“…It has been shown, that for CGB genes transcription in placenta, the most important seems to be 360 nucleotides long 5’UTR region with binding sites of transcription factors such as: SP1, SP3 and AP2, which regulate basal CGB expression [13, 22, 26, 34, 35]. Our previous results revealed strong correlations between TFAP2A transcripts and CGB1–9 as well as CGB3–9 mRNA levels in term placenta [13].…”

“…Still, it is known that SP1 and SP3 are factors which can extend opposite effects on CGB genes expression in trophoblast. Therefore, interpretation of the results obtained for cancers may not be so straightforward [22, 26]. Nevertheless, it cannot be excluded that similar mechanisms may regulate CGB gene expression during both pregnancy and in cancer.…”

“…Another aspect of CGB expression regulation by the placenta is the dependency on the access to selected transcription factors: ETS-2, SP1, SP3, AP2, OCT3/4, PPARγ, P53 and MTA3 and their binding capacity [20–26]. However, AP2, SP1 and SP3, are believed to be the key regulators of basal CGB transcription in placental trophoblast cells [20–26]. In fact, we have previously shown that, during pregnancy, expression of CGB genes strongly correlates with expression of the TFAP2A gene, encoding the AP2 transcription factor [13].…”

The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease

“…In this regard, new understanding of obesity development in female mouse knockout/knock-in models, and its dependence on diminished function of non-classical estrogen receptor (ER)-alpha [47], may suggest the marmoset as a particularly appropriate preclinical model. Of relevance is the marmoset’s naturally diminished signaling via ER-alpha due to intracellular inhibitory binding proteins for both ER-alpha and estrogen response elements on DNA [48]. Each provides clear potential by which manipulation of ER signaling may provide understanding of functional mechanism that is not possible in Old World monkeys.…”

“…Development of transgenic marmosets and marmoset stem cells has benefitted from recent revelations concerning marmoset reproductive physiology and a key difference to Old World primates, including humans. In marmosets, chorionic gonadotropin (CG) in addition to placental expression and maintenance of pregnancy [48], is also expressed by pituitary gonadotropins [59,60]. Episodic release of CG from the marmoset pituitary regulates ovarian follicle growth, triggers ovulation and supports corpus luteum function in females [59], and in males regulates testicular testosterone production in support of spermatogenesis [61].…”