Molecular endocrinology, chromatin, transcription, pituitary gland, reproduction.
Our research is aimed at understanding how hormones affect gene expression and cell function at the molecular level, and specifically the role and mechanism of targeting the chromatin. We are interested in the mechanisms through which regulatory hormones induce chromatin and epigenetic changes to affect various aspects of physiology, especially in the reproductive endocrine system. Our main model is the gonadotrope of the pituitary gland which controls reproduction through the production of the gonadotropic hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). Gonadotrope activity and the synthesis of these hormones are regulated primarily by the hypothalamic gonadotropin releasing hormone (GnRH), with additional feed-back regulation from gonadal hormones. Following a long period of quiescence since soon after birth, puberty signals a reawakening of gonadotrope activity and production of LH and FSH in response to elevated levels of GnRH. The gonadotrope thus provides a dynamic and hormone-inducible model for the regulation of gene expression which is mediated through changes at the level of the chromatin, transcription, splicing and post-translational modifications. Our current projects focus on establishing how LH and FSH genes are packaged and how GnRH modifies the chromatin via histone and DNA modifications, which form the basis for the epigenetic regulation of these genes. We are also studying the role of non-coding RNAs in this process. We work with cell lines in culture, primary cells and a limited amount of mouse work, and use molecular, proteomic and single-molecule biophysical tools. We are particularly interested to understand the importance of these mechanisms in diseases that affect human fertility.
1. Savulescu, D., Feng, J, Ping Y.S., Mai O., Boehm U., He B., O’Malley B.W., Melamed P. 2013. Gonadotropin-releasing hormone-regulated prohibitin mediates apoptosis of the gonadotrope cells. Mol. Endocrinol. 27:1856-70.
2. Melamed, P., Savulescu, D., Lim, S., Wijeweera, A., Luo, Z.J., Luo, M., Pnueli, L. 2012. Gonadotropin releasing hormone (GnRH)-signalling downstream of calmodulin. J. Neuroendocrinol. 24:1463-75.
3. Pnueli, L., Luo, M., Wang, S., Naor, Z. and Melamed, P. 2011. Calcineurin regulates expression of both subunits of the Follicle-Stimulating Hormone through distinct mechanisms. Mol. Cell. Biol. 31:5023-36.
4. Melamed, P. 2010. Hormonal signaling to FSHβ gene expression. Mol. Cell. Endocrinol. 314:204-12.
5. Luo, Z.J., Wijeweera, A., Oh, Y.Z., Liou, Y.C. and Melamed, P. 2010. Pin1 regulates gonadotropin β-subunit gene transcription through facilitating the phosphorylation-dependent ubiquitination of SF-1. Mol. Cell. Biol. 30:745-63.