Multiple promoter elements in the human chorionic gonadotropin β subunit genes distinguish their expression from the luteinizing hormone β gene

An, Hollenberg; Rg, Pestell; Albanese, Christopher; Me, Boers; Jameson, J. Larry

doi:10.1016/0303-7207(94)90192-9

Cited by 35 publications

(26 citation statements)

References 31 publications

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“…In the horse, the LH gene is expressed both in the pituitary and in the placenta, using the same transcriptional start site, which is homologous to that of the human LH gene (Sherman et al 1992), giving rise to identical transcript sizes. In a functioning CG /LH system it is assumed that, during evolution, changes within the promoter regions of CG genes have led to the placenta-specific expression, and the usage of a novel transcriptional start site for the CG gene yields transcripts of 1·1 kb (Jameson et al 1984, Hollenberg et al 1994. In the marmoset, the situation is very different.…”

Section: Discussionmentioning

confidence: 99%

Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

Müller¹,

Simoni²,

Pekel³

et al. 2004

Journal of Molecular Endocrinology

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The pituitary gonadotrophins LH and FSH are responsible for regulation of gametogenesis in the testis and ovary. Chorionic gonadotrophin (CG), a third closely related glycoprotein hormone derived by gene duplication of the LH gene and secreted by the placenta in primates, is essential for the rescue of the corpus luteum and maintenance of pregnancy. We have recently shown that marmoset (m) CG mRNA is highly expressed in the pituitary of the common marmoset (Callithrix jacchus) and that LH is less active than human CG in activating the human LH receptor lacking exon 10. To investigate further which gonadotrophin is the actual ligand of the LH receptor (LHR) of the marmoset monkey that naturally lacks exon 10, we identified and characterised the genomic organisation of the mLH gene and its expression. Intergenic PCR amplification of the region encompassing the mLH and the mCG genes revealed that, surprisingly, mCG is located 20 kbp upstream of the LH gene, whereas in other species the intergenic distance is approximately 2-3 kbp. Sequence analysis of the mLH coding region showed 70% identity to mCG and 90% identity to human LH at the amino acid level. Both gonadotrophin subunits are present at the genomic level, but RT-PCR of pituitary and placental total RNA using specific oligonucleotides for mCG and mLH showed high expression of mCG mRNA in both tissues, whereas LH was expressed neither in the pituitary nor in the placenta. Thus mLH mRNA is lacking in the marmoset pituitary. Immunohistochemistry of marmoset pituitaries showed that mCG was confined to the gonadotrophes, and partly co-localised in cells stained positively for FSH. Western blot analysis confirmed the presence of mCG in the pituitary. Northern blot analysis using mCG as a probe displayed one transcript of 0·7 kb in the pituitary and detected two transcripts of 1·1 kb and 2 kb in the marmoset placenta. Our results suggest that, in the common marmoset, CG is the only gonadotrophin with luteinising function that is present in the pituitary. We postulate that, owing to an unknown mutational event in evolution, expression of mLH was completely abolished, and CG -which, unlike LH, acts normally even when exon 10 is missing from the LHR -took over its function.

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Section: Discussionmentioning

confidence: 99%

Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

Müller¹,

Simoni²,

Pekel³

et al. 2004

Journal of Molecular Endocrinology

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“…While hCG␣ is encoded by a single gene on chromosome 6, hCG␤ can be encoded by a gene cluster of six (hCG␤1, -2, -3, -5, -7, and -8) paralogues on chromosome 19 (1). Recent studies have suggested that the expression of hCG␤5 and -8 may account for the majority of hCG␤ transcripts given that all hCG␤ paralogues share high sequence homology in their promoter regions (2,3).…”

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confidence: 99%

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

Cheong

Wang

Chuang

et al. 2016

Molecular and Cellular Biology

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e Human chorionic gonadotropin (hCG) is composed of a common ␣ subunit and a placenta-specific ␤ subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCG␤ expression, it remains unclear how cAMP stimulates placenta-specific hCG␤ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCG␤ paralogues by chromatin immunoprecipitation-on-chip (ChIPchip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCG␤ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCG␤ promoter and GCM1 but not TFAP2C. Indeed, the hCGcAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCG␤ expression and cell differentiation. Successful pregnancy requires a variety of hormones, growth factors, and cytokines to regulate uterine decidualization, embryo implantation, and pregnancy maintenance. For instance, progesterone and estrogen steroid hormones from the ovary prepare the uterine endometrium for embryo implantation. Human chorionic gonadotropin (hCG) is a critical hormone for pregnancy maintenance in humans. hCG is a glycoprotein hormone comprising ␣ and ␤ subunits. The hCG␣ subunit is shared with other glycoprotein hormones, including thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone (LH), whereas the hCG␤ subunit is specifically expressed in placenta and is unique to hCG. While hCG␣ is encoded by a single gene on chromosome 6, hCG␤ can be encoded by a gene cluster of six (hCG␤1, -2, -3, -5, -7, and -8) paralogues on chromosome 19 (1). Recent studies have suggested that the expression of hCG␤5 and -8 may account for the majority of hCG␤ transcripts given that all hCG␤ paralogues share high sequence homology in their promoter regions (2, 3).hCG expression can be detected in early 6-to 8-cell embryos, and this may serve as an embryonic signal for the rendering of appropriate maternal physiology for pregnancy (1). After implantation, the serum hCG level increases dramatically as pregnancy proceeds, reaching its peak at 9 or 10 weeks of gestation, and then decreases and remains at ϳ20% of the peak value until term (4). One of the crucial hCG functions is to stimulate progesterone synthesis from the corpus luteu...

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“…The gene encoding LHb subunit was cloned and sequenced in 1984, 1 and is located on chromosome 19. 2 Identification of mutations in key genes that regulate reproduction should explain many cases of infertility with unknown pathogenesis. Three genetic variants of LH were recently discovered.…”

Section: Introductionmentioning

confidence: 99%

Influence of missense mutation and silent mutation of LHβ-subunit gene in Japanese patients with ovulatory disorders

et al. 2003

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The frequency of variant LHb containing two point mutations (T 986 -C and T 1008 -C) and its relationship to reproductive disorders differ widely between ethnic groups. In a Japanese population, variant luteinizing hormone (LH) correlates with ovulatory disorders. Here we examined the relationship between two missense mutations and five silent mutations (C 894 -T, G 1018 -C, C 1036 -A, C 1098 -T and C 1423 -T) in the LHb gene, and ovulatory disorders. We studied 43 patients with ovulatory disorders, 79 patients with normal ovulatory cycles, and 23 healthy men who agreed to join our DNA analysis. PCR-amplified LHb-subunit gene sequences were compared with a base sequence of wild-type LH reported after direct sequencing. The highest frequency (0.945) of novel allele was observed at the position of the C 1036 -A transition. No homozygotes for wild-type LHb (C 1036 ) were identified. The frequency of novel allele in patients with polycystic ovary syndrome, endometriosis, premature ovarian failure and luteal insufficiency was significantly different from that of healthy women. The frequencies of novel alleles (C 894 -T, C 1098 -T and C 1423 -T) in patients with ovulatory disorders were significantly higher than those with normal ovulatory cycles. The mean incidence of point mutation in patients with ovulatory disorders was higher than in those with normal ovulatory cycles. Among patients with variant LH, five silent mutations were identified in 87.5% of patients with ovulatory disorders, whereas only a few silent mutations were identified in patients with normal ovulatory cycles. In a Japanese population, five silent mutations of variant LH could have influenced two missense mutations and/or other unknown missense mutations, causing ovulatory disorders.

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Multiple promoter elements in the human chorionic gonadotropin β subunit genes distinguish their expression from the luteinizing hormone β gene

Cited by 35 publications

References 31 publications

Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

Influence of missense mutation and silent mutation of LHβ-subunit gene in Japanese patients with ovulatory disorders

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