Developmental Activation of the Human Growth Hormone Gene Cluster in Pituitary and Placenta


Project Summary

The human growth hormone gene cluster consists of five genes. (See Figure 1.)

The most 5’ gene, hGH-N, is expressed in pituitary somatotrope cells, while the other four genes, CS-A, CS-B,CS-L and GH-V are selectively expressed in the syncytiotrophoblast cells of the placental villi. The expression of the entire cluster is under control of a set of five chromatin-based determinants collectively known as a ‘locus control region’. Each LCR determinant is marked by a DNaseI hypersensitive site in chromatin of the expressing cell type. The HS of the hGH LCR are located between 15 and 32 kb 5’ to the hGH cluster: HSI, II,III and V form in pituitary chromatin while a partially overlapping set of HSIII, IV, and V form in the chromatin of the placenta. The aim of our studies is to determine the role(s) and mechanisms of the hGH LCR components in the selective and robust activation and expression of the various genes of the hGH cluster in either the pituitary or the placenta.

A remarkable aspect of the growth hormone system is the close proximity of two other genes with distinct and mutually-exclusive tissue-specificities, scn4a (skeletal muscle) and Igβ (B-lymphocytes). Some of the hypersensitive sites that comprise the hGH LCR are situated in close proximity to, or within, these two unrelated genes. Thus the hGH chromosomal locus presents us with a complex and highly informative model for the study of gene regulation. Of particular interest is how the closely packed genes in this region are activated in a selective, robust, and mutually-exclusive manner. We are currently focusing on the role of chromatin structure and epigenetic modifications in this process.


Project Personnel

Brian Shewchuk, Ph.D. (Instructor in Genetics and recipient of an NIH KO1 award)
Yugong Ho, Ph.D. (Instructor in Genetics and recipient of an NIH KO1 award)
Atsushi P. Kimura, Ph.D.
Eung-Jae Yoo, Ph.D.
Daria Sizova, Ph.D.

Praveen Sethupathy

Rebecca Beerman


Selected References

Primary Papers (1995 - present)

  1. Bennani-Baiti, I.M., Jones, B.K., Cooke, N.E., Liebhaber, S.A.: Physical Linkage of the Human Growth Hormone (GH) Gene Cluster and the Skeletal Muscle Sodium Channel α-Subunit (SCN4A) Gene on Chromosome 17. Genomics 29: 647-652, 1995.

  2. Jones, B.K., Monks, B.R., Liebhaber, S.A., Cooke, N.E.: The Human Growth Hormone Gene is Regulated by a Multicomponent Locus Control Region. Mol. Cell. Biol., 15: 7010 -7021, 1995.

  3. Bennani-Baiti IM, Cooke NE, Liebhaber SA. Physical Linkage of the Human Growth Hormone Gene Cluster and the CD79b (Igβ/B29) Gene. Genomics 48:258-264, 1998.

  4. Bennani-Baiti IM, Asa SL, Song D, Iratni R, Liebhaber SA, Cooke NE. DNaseI-hypersensitive Sites I and II of the Human Growth Hormone Locus Control Region are a Major Developmental Activator of Somatotrope Gene Expression. Proc. Natl. Acad. Sci. U.S.A. 95:10,655-10,660, 1998.

  5. Shewchuk, B.M., Asa, S.L. Cooke, N.E., and Liebhaber, S.A. 1999. Pit-1 binding sites in the somatotrope-specific HS I,II region of the hGH locus are essential for in vivo LCR-mediated hGH-N gene activation. J. Biol. Chem., 274:35725-35733.

  6. Su, Y., Liebhaber, S.A., and Cooke, N.E. 2000. The human growth hormone gene cluster locus control region supports position-independent pituitary- and placenta-specific expression in the transgenic mouse. J. Biol. Chem., 275:7902-7909.

  7. Elefant, F.E., Cooke, N.E., and Liebhaber, S.A. 2000. Targeted recruitment and spreading of histone acetyltransferase activity by a locus control region. J. Biol. Chem., 275:13827-13834.

  8. Elefant, F.E., Su, Y., Liebhaber, S.A., and Cooke, N.E. 2000. Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region. EMBO J, 19: 6814-6822.

  9. Shewchuk, B., Cooke, N. and Liebhaber, S.A. 2001. The Human Growth Hormone Locus Control Region Mediates Long-Distance Transcriptional Activation Independent of Nuclear Matrix Attachment Regions". Nucleic Acids Research. 29:3356-3361.

  10. Ho, Y., Elefant, F., Cooke, N., and Liebhaber, S.A., 2002. A Defined Locus Control Region Determinant Links Chromatin Domain Acetylation With Long-Range Gene Activation. Molecular Cell. 9:291-302.

  11. Shewchuk, BM, Liebhaber SA, and Cooke, NE, 2002. Specification of unique Pit-1 activity in the hGH Locus Control Region. PNAS 99: 11784-11789

  12. Kimura A. P., Liebhaber S.A, and Cooke, N. E. 2004. Epigenetic Modifications at the Human Growth Hormone Locus Predict Distinct Roles for Histone Acetylation and Methylation in Placental Gene Activation. Mol Endocrinology 18:1018-1032 (Cover featured).

  13. Cajiao, I., Zhang, I., Yoo, E J, Cooke NE., and Liebhaber, S.A. Bystander Gene Activation by a Locus Control Region. Embo. J. In Press 2004.

  14. Ho, Yugong, Elefant Felice, Liebhaber Stephen A, and Nancy E. Cooke. 2006 Locus Control Region Transcription Plays an Active Role in Long-range Gene Activation.  Molecular Cell. 23:365-75 Download PDF

  15. Eung Jae Yoo, Cajiao Isabela, Kim Jeong-Seon, Kimura Atsushi P, Zhang Aiwen, Cooke Nancy E., and Stephen A. Liebhaber. 2006. Tissue-specific Chromatin Modifications at a Multigene Locus Generate Asymmetric Transcriptional Interactions. Mol Cell Biol.  26:5569-5579. Download PDF

  16. Shewchuk Brian M., Ho Yugong, Liebhaber Stephen A. and Cooke Nancy E. 2006. A single base difference between Pit-1 binding sites at the hGH promoter and locus control region specifies distinct Pit-1 conformations and functions. Mol Cell Biol. In Press. Download PDF


Reviews (1993 - present)

  1. Cooke, N.E.: Chapter 23: "Prolactin: Basic Physiology", in DeGroot, L.J., ed., Endocrinology, 3rd Edition, W.B. Saunders Co., Philadelphia, PA, 1993, pp. 368-393.

  2. Cooke, N.E., Jones, B.K., Salzman, A., Russell, J.E., Misra-Press, A., Urbanek, M., Liebhaber, S.A.: Chapter 11: "The Gestational Physiology of the Growth Hormone Gene Family" in Adashi, E.Y., Thornton, M.O., eds. The Somatotrophic Axis and the Reproductive Process in Health and Disease, Springer-Verlag, New York, 124 - 141, 1995.

  3. Cooke, N.E. and Liebhaber, S.A.: Chapter 1: "Growth Hormone Gene Expression in Pituitary and Placenta" in Shiverick, K.T., Rosenbloom, A.L., eds., Human Growth Hormone: Basic and Clinical Aspects, CRC Press, Boca Raton, FLA, 1 -12, 1995.

  4. Cooke, N.E. and Liebhaber, S.A.: "Molecular Biology of the Growth Hormone - Prolactin Gene System", in Litwack G., ed., Vitamins and Hormones, 50: 385 - 459, 1995.

  5. Salzman, A. and Cooke, N.E.: Chapter 35. Prolactin in Adashi, E.Y., Rock, J.A., Rosenwaks, Z., eds., Reproductive Endocrinology, Surgery and Technology, Lippincott-Raven Press, Philadelphia, PA, 1996, pp. 747-768.

  6. Cooke NE, Liebhaber SA. Chapter 7. Regulation of Growth Hormone Gene Expression, in Kostyo J.L., (ed.). Hormonal Control of Growth, Handbook of Physiology, Oxford University Press, New York, pp 165-188, 1999.

  7. Cooke, N.E. and Liebhaber, S.A. 2001. Locus Control Regions. In Encyclopedia of Molecular Medicine. John Wiley and Sons, Inc. Vol 5, pages 1953-1956.

  8. Ho Y, Liebhaber SA., and Cooke N.E. Activation of the human GH gene cluster: roles for targeted chromatin modification. Trends in Endocrinology and Metabolism, In Press 2004