Program
Summary
Pituitary growth hormone (GH-N) plays a central role in the regulation of growth and development during childhood, and is also a critical regulator of glucose and lipid metabolism throughout life. The placentally-expressed human GH-variant gene (hGH-V) is similarly thought to contribute to glucose and lipid metabolism during pregnancy. To further understand how these GHs regulates these processes, we have undertaken a detailed study of how the hGH-N gene is turned on and regulated in pituitary somatotropes, and hGH-V in the placental syncytiotrophoblast. We have demonstrated in our published studies that the hGH gene cluster is regulated by a locus control region (LCR) located 5' to this multigene locus. This hGH LCR is made up of five DNaseI hypersensitive sites present in the chromatin of placenta, pituitary, or both tissues. When this region is present in a transgenic construct, mouse lines carrying the transgene consistently express the hGH-N gene in the pituitary and the hGH-V and hCS genes in the placenta. Remarkably, this expression is at normal levels, is regulated, is copy-number-dependent, and site-of-integration independent indicating that the LCR is able to establish an autonomous chromatin environment anywhere in the mouse genome.
The overall goal of our current work is to understand the mechanisms by which this LCR modulates the structure of chromatin at the hGH locus in the pituitary and placenta. We are currently studying three main questions. The first addresses the function of non-coding RNA transcripts that are transcribed through the active LCR region, which we have shown play an essential role in LCR-mediated activation of the hGH-N gene. The second area addresses the function of the CD79b gene. This is a lymphocyte-specific gene that lies between the 5 gene hGH cluster and the major pituitary-specific LCR elements, HSI,II. CD79b encodes a subunit of the B-cell receptor (Ig?) and the only known site of Ig? protein expression is in B lymphocytes. Surprisingly, we have discovered that this gene is activated in pituitary somatotropes by an epigenetically-based "bystander" mechanism. Of particular interest is the observation that CD79b is expressed robustly as mRNA in somatotropes, but no Ig? protein is produced. We will test the hypothesis that CD79b transcription in the pituitary plays a role in hGH LCR function, hGH-N activation, and regulation.
The final area is to determine the role of the LCR in regulating the placental members of the GH cluster. Although hGH-N and the placentally-expressed genes in the hGH cluster share elements of the LCR, it is now clear that the pathways of LCR activation in the two tissues are quite different. These studies, taken together, should result in a detailed understanding of the regulation of the hGH/hCS cluster by its LCR via chromatin remodeling and epigenetic processes. This will serve as a foundation for a sophisticated understanding of the physiology and pathophysiology of hGH expression and pituitary development. These insights should establish a foundation for the subsequent design of new approaches to medical intervention for disorders affecting corresponding hormonal circuits.
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Cajiao I, Zhang A, Yoo EJ, Cooke NE, Liebhaber SA. Related Articles, Links Bystander gene activation by a locus control region.
EMBO J. 2004 Sep 29;23(19):3854-63. Epub 2004 Sep 09.
PMID: 15359275 [PubMed - in process]
Su Y, Balice-Gordon RJ, Hess DM, Landsman DS, Minarcik J, Golden J, Hurwitz I, Liebhaber SA, Cooke NE. Neurobeachin is essential for neuromuscular synaptic transmission. J Neurosci. 2004 Apr 7;24(14):3627-36. PMID: 15071111 [PubMed - indexed for MEDLINE]
Kimura AP, Liebhaber SA, Cooke NE. Epigenetic modifications at the human growth hormone locus predict distinct roles for histone acetylation and methylation in placental gene activation. Mol Endocrinol. 2004 Apr;18(4):1018-32. Epub 2004 Jan 08. PMID: 14715931 [PubMed - indexed for MEDLINE]
Ho Y, Liebhaber SA, Cooke NE. Activation of the human GH gene cluster: roles for targeted chromatin modification. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):40-5. Review. PMID: 14693425 [PubMed - indexed for MEDLINE]
Shewchuk BM, Liebhaber SA, Cooke NE. Specification of unique Pit-1 activity in the hGH locus control region. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11784-9. Epub 2002 Aug 20. PMID: 12189206 [PubMed - indexed for MEDLINE]
