Postdoctoral Position Available

Anthony Imbalzano, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cell Biology

Other Affiliation(s):
   Interdisciplinary Graduate Program

Chromatin Structure and Regulation of Gene Expression, Cell Cycle, Cell Differentiation, and Oncogenesis

The main focus of our research is to understand how factors that regulate the opening and closing of chromatin structure affect a diverse set of biological processes, including gene expression, cell cycle progression, initiation of cellular differentiation, tumorigenesis, and mouse development.  Most of our work focuses on the mammalian SWI/SNF complexes, which are multi-subunit, ATP-dependent enzymes that alter chromatin structure.  These evolutionarily conserved enzymes physically alter the structure of chromatin to regulate gene expression.  Surprisingly, component subunits of these enzymes can interact with known tumor suppressors to regulate cell growth and also can act as tumor suppressors themselves.  Some subunits are required for embryogenesis.  Additionally, SWI/SNF proteins can be targeted by viral regulatory proteins upon infection of cells by diverse viruses such as HIV, HPV and EBV.

Our past research efforts have reported isolation of human SWI/SNF complexes and functional characterization of their ability to alter in vitro assembled chromatin templates and promote transcription factor interactions with the template.  Work on the mechanism of SWI/SNF mediated chromatin remodeling is ongoing in the lab, with specific interest in how post-translational histone modifications affect chromatin remodeling.  To address biological function of these enzymes, we created cell lines that inducibly express mutant forms of the enzymes and are utilizing them to examine the role of these enzymes in numerous gene activation and cellular differentiation events.  In particular, we have observed that expression of the mutant SWI/SNF chromatin remodeling enzymes prevents muscle and adipose differentiation.  Detailed examination of the temporal interplay between tissue specific regulatory factors and diverse chromatin remodeling enzymes is in progress (see figure).  To date, we have identified disparate functions for SWI/SNF enzymes at different promoters, including facilitation of pol II pre-initiation complex function and facilitation of activator binding to the promoter.

In addition, we are continuing our efforts to assess the function of the SWI/SNF subunit termed Ini1.  Ini1 is missing or mutated in a number of pediatric rhabdoid and other tumors, suggesting it acts as a tumor suppressor.  In collaboration with Steve Jones’ lab, we previously showed that approximately 15% of mice heterozygous for Ini1 exhibit tumors, predominantly in the head and neck region, demonstrating that Ini1 does act as a tumor suppressor.  Ini1 null embryos die around the time of implantation in the womb, indicating that Ini1 is essential for normal mouse development.  However, analysis of SWI/SNF function in Ini1 deficient cells derived from patient tumors shows that multiple SWI/SNF functions are unaffected by the absence of Ini1.  Further analyses of ini1 function and the regulation of Ini1 expression are in progress.

Figure

Temporal order of events during activation of the PPARgamma gene during adipogenesis
(see Salma et al, MCB 24:4641, 2004)

Recent Publications

Hill, DA, CL Peterson, and AN Imbalzano. 2005. Effects of HMGN1 on chromatin structure and SWI/SNF-mediated chromatin remodeling. J. Biol. Chem. 280:41777-41783.

Imbalzano, AN and SN Jones.  2005.  Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability.  Cancer Cell.  7:294-295.  (Preview)

de la Serna, IL, Y Ohkawa, CA Berkes, DA Bergstrom, CS Dacwag, SJ Tapscott, and AN Imbalzano.   2005.  MyoD targets chromatin remodeling complexes to the myogenin locus prior to forming a stable DNA-bound complex.  Mol. Cell Biol.  25:3997-4009.

Salma, N, H Xiao, E Mueller, and AN Imbalzano.  2004.  Temporal recruitment of transcription factors and SWI/SNF chromatin remodeling enzymes during adipogenic induction of the PPARg nuclear hormone receptor.  Mol. Cell. Biol.  24:4651-4663.

Doan, DN, TM Veal, Z Yan, W Wang, SN Jones, and AN Imbalzano.  2004.  Loss of the INI1 Tumor Suppressor Does Not Impair the Expression of Multiple BRG1-dependent Genes or the Assembly of SWI/SNF Enzymes.  Oncogene.  23:3462-3473.

Guidi, CJ, TM Veal, SN Jones, and AN Imbalzano.  2004.  Transcriptional compensation for loss of an allele of the Ini1 tumor suppressor.  J. Biol. Chem.   279:4180-4185.

Roy, K, IL de la Serna, and AN Imbalzano.   2002.  The myogenic basic helix-loop-helix family of transcription factors show similar requirements for SWI/SNF chromatin remodeling enzymes during muscle differentiation in culture. J. Biol. Chem.   277:33818-33824.

de la Serna, IL, K Roy, KA Carlson, and AN Imbalzano.   2001.  MyoD can induce cell cycle arrest but not muscle differentiation in the presence of dominant negative SWI/SNF chromatin remodeling enzymes.  J. Biol. Chem.  276: 41486-41491.

Guidi, CJ, AT Sands, BP Zambrowicz, TT Turner, DA Demers, W Webster, T Smith, AN Imbalzano, and SN Jones.  2001.  Disruption of Ini1 leads to peri-implantation lethality and head and neck tumors in mice.  Mol. Cell. Biol.  21:3598-3603.

de la Serna, IL, KA Carlson, and AN Imbalzano.   2001. Mammalian SWI/SNF chromatin remodeling complexes promote MyoD-mediated muscle differentiation.  Nature Genetics   27:187-190.

Hill, DA and AN Imbalzano.   2000.  Human SWI/SNF nucleosome remodeling activity is partially inhibited by linker histone H1.  Biochemistry  39:11649-11656.

de la Serna, IL, KA Carlson, DA Hill, CJ Guidi, RO Stephenson, S Sif, RE Kingston, and AN Imbalzano.  2000.  Mammalian SWI/SNF complexes contribute to activation of the hsp70 gene.  Mol. Cell. Biol.  20:2839-2851.

Rotation Projects

Project #1        The initiation of new programs of gene expression in differentiating cells requires chromatin remodeling enzymes in addition to tissue specific transcription factors.  Characterization of the temporal events leading to gene activation during myogenesis and adipogenesis is ongoing using cell line models for differentiation.  In vitro work with purified components is also ongoing to address mechanism of action.  Multiple projects involving the role of chromatin remodeling enzymes during tissue specific gene expression are available.

Project #2         Loss of the Ini1 subunit of SWI/SNF enzymes in children causes malignant rhabdoid tumors.  In mice, targeted elimination of Ini1 results in early embryonic lethality and mice heterozygous for Ini1 are susceptible to tumor formation.  Attempts to understand the function of the Ini1 protein in gene expression, chromatin remodeling, cell cycle regulation, development, and oncogenesis are in progress using molecular biology, biochemistry, and mouse modeling.   

Laboratory Personnel

Current Personnel

Previous Trainees

Academic Background

Office: S1-842A
Phone: 508-856-1029
Fax: 508-856-5612
E-mail: Anthony.Imbalzano@umassmed.edu
Keywords: Cancer Biology, Gene Expression, Nuclear Architecture, Developmental Biology, Gene Regulation

More on Anthony Imbalzano's Research Research | Figures | Publications | Rotations | Personnel | Biography View All Sections on One Page

Postdoctoral Position Available POSTDOCTORAL POSITIONS Chromatin Remodeling Enzymes, Gene Expression & Cell Differentiation A position is available to examine the mechanisms by which histone modifying and ATP dependent chromatin remodeling enzymes promote gene-specific and higher order chromatin structural changes during the activation of genes that are required for cellular differentiation (see EMBO J 25:490; MCB 27:384; JBC 282:6564 MCB 29:1909).  Current emphasis is on skeletal muscle and adipose differentiation. Good verbal and written English skills are required.  Send c.v. and contact information for 3 references to: Anthony N. Imbalzano, Ph.D. Department of Cell Biology UMassMedicalSchool 55 Lake Avenue North Worcester, MA 01655 Email: anthony.imbalzano@umassmed.edu   POSTDOCTORAL POSITION – IMMEDIATE OPENING Molecular Mechanisms of Breast Tissue Differentiation and Oncogenesis A position is available immediately to examine the mechanisms controlling breast tissue differentiation, maintenance, and tumorigenesis, with an emphasis on gene regulatory pathways, and higher order chromatin and nuclear structure using an approach intergrating cell and molecular biology.  Good verbal and written English skills are required.  Send c.v. and contact information for 3 references to: Jeffrey A. Nickerson, Ph.D. or Anthony N. Imbalzano, Ph.D., Department of Cell Biology UMass  Medical  School 55 Lake Avenue North Worcester, MA  01655 Email: anthony.imbalzano@umassmed.edu or jeffrey.nickerson@umassmed.edu