Nancy E. Cooke, M.D.
Departments of Medicine and Genetics
Transgenic and Chimeric Mouse Facility

752b Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6149

Tel: (215) 898-4425
Fax: (215) 573-5809
Email: necooke@mail.med.upenn.edu

Stephen A. Liebhaber, M.D.
Departments of Genetics and Medicine
Transgenic and Chimeric Mouse Facility

428 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145

Tel: (215) 898-7834
Fax: (215) 573-5157
Email: liebhabe@mail.med.upenn.edu


Developmental Activation of the Human Growth Hormone Gene Cluster in Pituitary and Placenta.
The Growth Hormone group is investigating the pathways of developmental activation of mammalian gene expression. The human Growth Hormone ( hGH ) cluster contains 5 genes that are selectively and robustly expressed in a developmentally-defined progression in either pituitary somatotropes ( hGH-N ) or placental syncytiotrophoblasts ( hCS-A, hCS-B, hCS-L , and hGH-V ). Studies focus on identification of pathways of chromatin activation, the roles and mechanisms of the various components of the hGH LCR in gene activation in the two tissues, and the role of epigenetic mechanisms in these pathways. Recent interest has also expanded to the B-cell specific Igβ gene; this gene is situated between the hGH cluster and the hGH LCR (see figure of the locus). Problems of gene transcriptional insulation, ectopic expression, and evolution of gene expression profiles in the pituitary, placenta, and B-lymphocytes are being challenged via these studies.

Mechanisms of mRNA Stabilization and Post-transcriptional Control
The mRNA stability group is attempting to define RNA-protein complexes (RNPs) that are critical determinants of mRNA stability and function. The specific model being studied is the long-lived and erythroid-specific human α-globin mRNA. There is now much evidence that the stability of α-globin mRNA is mediated by the formation of a sequence-specific RNP complex at a defined site in the 3' UTR. The bound protein, αCP, is in the KH domain class of RNA-binding proteins. Our studies have shown that the mRNP α-complex' determinant appears to be involved in a wide array of stabilization and translational control mechanisms. We are now involved in establishing the full spectrum of αCP target mRNAs, the roles of the corresponding interactions in mRNA processing and expression, and the mechanisms that underlie these processes.

Vitamin D-Binding Protein (DBP) Gene Expression;
Defining the Pathway of hDPB Locus Activation in Hepatic Chromatin and Assigning Novel Physiologic Functions to DBP

The DBP group studies Vitamin D-binding protein (DBP, also known as the group-specific component of serum: GC-globulin). This is a highly expressed serum protein that is a member of the albumin (ALB), α-fetoprotein (AFP), and afamin or α-albumin (AFM) gene family. These four genes are linked on human chromosome 4. DBP is a highly polymorphic serum protein predominantly synthesized in liver as a single-chain glycoprotein of approximately 58 kDa. Studies include: the function of DBP via gene knock-out and transgenic approaches in mice, and the basis for its robust and liver-specific transcriptional activation via defined chromatin determinants.

Last Updated: Friday, 27 August 2004