Mechanisms of hormonally-induced transcription of LHBeta subunit gene in its chromatin setting

Master'sMASTER OF SCIENC

Cross Talk in Hormonally Regulated Gene Transcription through Induction of Estrogen Receptor Ubiquitylation

Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ERα) on the mammalian LHβ gene has remained poorly defined. We demonstrate here that ERα can associate with the LHβ promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERα ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ERα on the LHβ promoter. The ERα association and transactivation of the LHβ gene, as well as ERα degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERα ubiquitylation and subsequent transactivation of the LHβ gene can be induced by increasing the levels of the E2 enzyme as a result of signaling by an extracellular hormone, thus providing a new form of cross talk in hormonally stimulated regulation of gene expression

Distinct Mechanisms Involving Diverse Histone Deacetylases Repress Expression of the Two Gonadotropin β-Subunit Genes in Immature Gonadotropes, and Their Actions Are Overcome by Gonadotropin-Releasing Hormone▿

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced in the embryonic pituitary in response to delivery of the hypothalamic gonadotropin releasing hormone (GnRH). GnRH has a pivotal role in reestablishing gonadotropin levels at puberty in primates, and for many species with extended reproductive cycles, these are reinitiated in response to central nervous system-induced GnRH release. Thus, a clear role is evident for GnRH in overcoming repression of these genes. Although the mechanisms through which GnRH actively stimulates LH and FSH β-subunit (FSHβ) gene transcription have been described in some detail, there is currently no information on how GnRH overcomes repression in order to terminate reproductively inactive stages. We show here that GnRH overcomes histone deacetylase (HDAC)-mediated repression of the gonadotropin β-subunit genes in immature gonadotropes. The repressive factors associated with each of these genes comprise distinct sets of HDACs and corepressors which allow for differentially regulated derepression of these two genes, produced in the same cell by the same regulatory hormone. We find that GnRH activation of calcium/calmodulin-dependent protein kinase I (CaMKI) plays a crucial role in the derepression of the FSHβ gene involving phosphorylation of several class IIa HDACs associated with both the FSHβ and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH β-subunit gene is not CaMK dependent. This demonstration of HDAC-mediated repression of these genes could explain the temporal shut-down of reproductive function at certain periods of the life cycle, which can easily be reversed by the actions of the hypothalamic regulatory hormone

Gonadotropin-releasing hormone activation of C-jun, but not early growth response factor-1, stimulates transcription of a luteinizing hormone β-subunit gene

10.1210/en.2006-0022Endocrinology14773598-3605ENDO

The Singapore national precision medicine strategy

Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.Agency for Science, Technology and Research (A*STAR)Ministry of Health (MOH)National Medical Research Council (NMRC)National Research Foundation (NRF)We thank all investigators, staf members and study participants of the contributing cohorts and studies: (1) the HELIOS study at the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; (2) the GUSTO study jointly hosted by the National University Hospital, KK Women’s and Children’s Hospital, the National University of Singapore and the Singapore Institute for Clinical Sciences, the Agency for Science Technology and Research (A*STAR); (3) the SEED cohort at the Singapore Eye Research Institute; (4) the MEC, National University of Singapore; (5) the PRISM cohort; and (6) the TTSH Personalised Medicine Normal Controls cohort. We also thank the National Supercomputing Centre, Singapore (https://www.ncss.sg) for computation resources. The SG10K_Health project is funded by the Industry Alignment Fund (Pre-Positioning) (IAF-PP, H17/01/a0/007); the project made use of participating study cohorts supported by the following funding sources: (1) the HELIOS study by grants from a Strategic Initiative at Lee Kong Chian School of Medicine, the Singapore MOH under its Singapore Translational Research Investigator Award (NMRC/STaR/0028/2017) and the IAF-PP (H18/01/a0/016); (2) the GUSTO study by the Singapore National Research Foundation under its Translational and Clinical Research Flagship Program and administered by the Singapore MOH’s National Medical Research Council Singapore (NMRC/TCR/004-NUS/2008, NMRC/ TCR/012-NUHS/2014) with additional funding support available through the A*STAR and the IAF-PP (H17/01/a0/005); (3) the SEED study by NMRC/CIRG/1417/2015, NMRC/CIRG/1488/2018 and NMRC/OFLCG/004/2018; (4) the MEC by individual research and clinical scientist award schemes from the Singapore National Medical Research Council (including MOH-000271-00) and the Singapore Biomedical Research Council, the Singapore MOH, the National University of Singapore and the Singapore National University Health System; (5) the PRISM cohort study by NMRC/CG/ M006/2017_NHCS, NMRC/STaR/0011/2012, NMRC/STaR/0026/2015, the Lee Foundation and the Tanoto Foundation; and (6) the TTSH cohort study by NMRC/CG12AUG2017 and CGAug16M012. This research is also supported by the National Research Foundation Singapore under its NPM program Phase II funding (MOH-000588) and administered by the Singapore MOH’s National Medical Research Council