MCB Accepts, published online ahead of print on 16 July 2007

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimura, A. P. Articles by Liebhaber, S. A. Search for Related Content PubMed PubMed Citation Articles by Kimura, A. P. Articles by Liebhaber, S. A.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.00273-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Epigenetic activation of the human growth hormone gene cluster during placental cytotrophoblast differentiation

Atsushi P. Kimura, Daria Sizova, Stuart Handwerger, Nancy E. Cooke, and Stephen A. Liebhaber^*

Departments of Genetics and Medicine, University of Pennsylvania, Philadelphia, PA 19104, Department of Endocrinology, Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

^* To whom correspondence should be addressed. Email: liebhabe{at}mail.med.upenn.edu.

The hGH cluster contains a single pituitary growth hormone (hGH-N) gene and four placenta-specific paralogs. Activation of the cluster in both tissues depends on 5'-remote regulatory elements. The pituitary-specific locus control elements, HSI and HSII, located 14.5 kb (-14.5) 5' to the cluster, establish a continuous domain of histone acetylation that extends to, and activates hGH-N in the pituitary. In contrast, histone modifications in placental chromatin are restricted to the more 5'-remote HSV-HSIII (-28 to -32 kb) and to the placentally-expressed genes in the cluster with minimal modification between these two regions. These data predict distinct modes of hGH cluster gene activation in pituitary and placenta. Here we used cell culture models to track structural changes at the hGH locus through placental gene activation. The data revealed that this process was initiated in primary cytotrophoblasts by histone H3K4 di- and tri-methylation and H4 acetylation restricted to HSV and to the individual placental gene repeat (PGR) units within the cluster. Later stages of transcriptional induction were accompanied by enhancement and extension of these modifications, and by robust H3 acetylation at HSV, HSIII, and throughout the placental gene regions. These data suggested that elements restricted to HSIII-HSV regions and each individual PGR might be sufficient for activation of the hCS genes. This model was tested by comparing hCS transgene expression in the placentas of mouse embryos carrying a full hGH cluster to those in which HSIII-HSV was directly linked to the individual hCS-A PGR unit. The findings indicate that the HSIII-HSV region and the PGR units, although targeted for initial chromatin structural modifications, are insufficient to activate gene expression and that this process is dependent on additional, as yet unidentified, chromatin determinants.

This article has been cited by other articles:

• Kumar, P., Kamat, A., Mendelson, C. R. (2009). Estrogen Receptor {alpha} (ER{alpha}) Mediates Stimulatory Effects of Estrogen on Aromatase (CYP19) Gene Expression in Human Placenta. Mol. Endocrinol. 23: 784-793 [Abstract] [Full Text]