Genetics and Gene Regulation Program

Address

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

Office tel.: 215 898-7834
Lab tel.: 215 898-8577
Fax: 215 573-5157
E-mail: liebhabe@mail.med.upenn.edu

Link(s)

Lab's home page

Dept of Genetics

Education

Brandeis University, BA, (Chemistry), 1968

Yale University, MD, 1972

Research Interests

• Roles of chromatin structure and epigenetic controls in eucaryotic gene activation
• Roles of mRNA-protein interactions in control of eucarytic mRNA stability and expression

Key words Chromatin structure, histone modifications, Growth Hormone gene, pituitary, placenta, transcriptional controls, mRNA expression, αCP RNA binding proteins, mRNA stability, globin mRNA.

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Description of Research

Roles of chromatin structure and epigenetic controls in eucaryotic gene activation

In eukaryotic organisms gene regulation is dependent upon developmentally controlled alterations in chromatin structure. Epigenetic modifications in histones and DNA result in selective activation of gene expression profiles. In many cases these modifications in chromatin structure result in long-range control of gene promoters, reaching over hundreds of kbs. Understanding how these epigenetic modifications are themselves controlled and the mechanisms by which they selectively activate and/or silence cohorts of genes is central to our understanding of development and cellular differentiation. We are approaching these questions using as a model the human Growth Hormone gene cluster. The genes in this cluster are robustly expressed, physiologically controlled, and highly specific to either pituitary somatotropes or placental syncytiotrophoblasts. These controls are conserved between mouse and human. Thus our studies are heavily dependent on the use of transgenic mouse models and are complemented where appropriate with in vitro chromatin analyses and cell culture models.

Recent Publications

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

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. 26: 6535-6546.

Kimura Atsushi P., Sizova Daria, Handwerger Stuart, Cooke Nancy E. and Stephen A. Liebhaber. 2007. Epigenetic activation of the human Growth hormone gene cluster during placental cytotrophoblast differentiation. Mol Cell. Biol. In Press.

Roles of mRNA-protein interactions in control of eucaryotic mRNA stability and expression

At any given level of gene transcription, the final level of expression for a particular gene can be altered over a span of several orders of magnitude by modulation in mRNA stability or translational control. For example the half-lives of specific mammalian mRNAs can be as sort as 15 minutes and as long as several days. Such post-transcriptional controls are dependent on sequence specific interactions between RNA binding proteins and target mRNAs. We are using a series of model mRNAs and expression systems to explore the role of a specific and highly abundant family of mRNA binding proteins, the αCPs, in mRNA stabilization and translational control. These studies are based on in vitro RNA-protein interaction assays and cell-based expression models. Comprehensive studies of αCP functions are being carried out using immunoaffinity RNP-isolation, Affymetrix chip expression platforms, artificial tethering of RNA binding proteins to mRNAs, and biochemical analysis of RNP sub-localization. We are also applying what we learn in these studies to design approaches to targeted modulation of gene expression in vivo using RNA 'decoys'. The analysis of mRNA decay is also revealing novel pathways of mRNA surveillance and mRNA structural modification that impact on the expression of both wild-type and mutant gene expression.

Recent Publications

Ji, Xinjun, Kong Jian, Carstens Russ P., and Stephen A. Liebhaber. 2007. The 3’UTR Complex Involved in Stabilization of Human α-Globin mRNA Assembles in the Nucleus and Serves an Independent Role as Splice-Enhancer. Mol Cell Biol. 27:3290-3302.

Kong, J and Liebhaber, SA. 2007. A Cell-type Restricted mRNA Surveillance Pathway Triggered by Ribosome Extension into the 3’ Untranslated Region. Nature Structural and Molecular Biology. 14:670-676.

Lab

Rotation Projects

Lab rotations are available in both the areas of chromatin structure/gene activation and in the area of mRNA-protein interactions/mRNA stability control. Students are encouraged to contact Dr. Liebhaber directly to discuss potential projects for rotation studies.

Lab personnel:

Please see our lab web-site for this information. Our laboratory has a steady state of approximately 10 doctoral and postdoctoral scientists.