Cancer, Stem Cell and Bone Biology Program
Gary S. Stein, PhD, is the Professor and Chair of the Department of Biochemistry at the University of Vermont (UVM) and Co-Director of the UVM Cancer Center. The central theme of Gary Stein’s research has been to discover mechanisms controlling proliferation and differentiation with emphasis on compromised regulation that is linked with disease. From the earliest stages of his career, he has pioneered characterization of transcriptional regulation that mediates cell cycle control. His studies have provided considerable insight into the molecular mechanisms regulating gene expression during the cell cycle at the G1/S phase transition in normal and tumor cells. He has characterized the unique parameters of cell cycle control that govern proliferation in human embryonic stem cells and reprogrammed pluripotent cells. The second field in which Gary Stein has had major and lasting impact is skeletal biology, where he established the foundation for addressing bone tissue specific gene expression, and provided valuable insight into aberrations that accompany the onset and progression of skeletal disease and tumor metastasis to bone. Furthermore, he has been instrumental in defining functional relationships between the nuclear organization of regulatory networks and gene expression that are mediated by transcription factors, coregulatory proteins and microRNAs. He has made seminal contributions to mechanisms that support combinatorial organization and assembly of regulatory machinery for gene expression in nuclear microenvironments and epigenetic control of cell fate and lineage commitment in biological control and cancer.
Gary Stein has published more than 800 papers in leading biomedical journals and edited more than 15 books. “Human Stem Cell Technology and Biology: A Research Guide and Laboratory Manual” was recently published by Wiley-Blackwell. This book comprehensively presents the biology of stem cells, the laboratory skills required for stem cell investigation and insight into the potential application of stem cells for treating diseases that are not responsive to conventional therapies.
Gary Stein has organized and chaired numerous international research conferences, and serves on advisory panels for United States and foreign government science policy and granting agencies, scientific advisory boards for biotechnology, pharmaceutical and health care organizations, and editorial boards of more than 16 journals. Throughout his career he has been committed to providing mentorship to more than 100 graduate students, postdoctoral students, and physician/scientists, developing research and science education programs in his institution as well as with universities in Europe, Asia, the Middle East and South America.
Dr. Stein directs a research program of 45 basic scientists and physician/investigators who are dedicated to discovering aberrant regulatory mechanisms in cancer cells and developing new dimensions to cancer diagnosis and therapy. His research program is sponsored by the National Cancer Institute and by research foundations. He is principal investigator of two program project grants and several R01 grants from the National Institutes of Health.
Our research group examines the molecular etiology of cancer, the basic biology of stem cells as it relates to regenerative medicine, and the biology of bone development and skeletal disorders.
At the cellular level, we focus on nuclear architecture as it supports proliferation and differentiation of lineage-committed cells and stem cells, as well as compromised nuclear structure that characterizes cancer cells. These studies analyze subnuclear organization of gene regulatory machinery including intranuclear trafficking of transcription factors, interactions with cell-signaling responsive co-factors and chromatin remodeling enzymes.
At the molecular level, we are defining epigenetic chromatin modifications at gene loci during interphase (‘Histone Code’) and mitosis (‘Bookmarking’) to understand transcriptional regulation of tissue-specific genes, cell cycle control and cell fate determination. Our studies center on transcriptional master regulators and post-transcriptional mechanisms (including microRNAs) that together control osteogenesis, hematopoiesis and the pluripotent state of embryonic stem cells. The aberrant loss- or gain-of-functions of these gene regulatory factors in leukemias, as well as in metastasizing breast, prostate and bone cancers, are being actively pursued.
We utilize a variety of cutting-edge cellular, molecular, biochemical and genetic approaches to address our biological questions. The in vivo mouse models we develop, together with ex vivo bone organ cultures and primary cell culture, permit pursuit of translational approaches to treat skeletal and hematopoietic disorders. Our experimental strategies involve state-of-the-art genomics (DeepSeq, ChIPSeq, Affymetrix) and proteomics analyses, as well as high resolution and live-cell imaging fluorescence microscopy.
A central theme of our research program is control of cell proliferation and differentiation with emphasis on mammalian development and compromised regulation that is linked to disease. We pioneered characterization of transcriptional regulation that mediates cell cycle control. Currently, the laboratory is investigating gene regulatory mechanisms that control competency for cell cycle progression at the G1/S phase transition in normal and tumor cells, as well as in human embryonic stem cells that have a characteristic abbreviated pluripotent cell cycle.
A second field in which our laboratory is making a major impact is skeletal biology, where we established the foundation for addressing bone tissue specific gene expression. Current initiatives include microRNA-mediated control and molecular, cellular, biochemical and in vivo genetic parameters of skeletal development and bone remodeling, aberrations that accompany the onset and progression of skeletal disease, as well as perturbations related to breast and prostate cancer metastasis to bone.
Our research group has been instrumental in defining functional relationships between subnuclear organization of regulatory proteins and gene expression. We have made important contributions to mechanisms that mediate combinatorial organization and assembly of regulatory machinery for gene expression in nuclear microenvironments. Currently, we are examining how nuclear architecture supports epigenetic control of cell fate and lineage commitment in biological control and cancer. The architectural parameters of regulatory networks that are obligatory for fidelity of gene expression are being clarified as a basis for therapeutic strategies with high specificity and reduced off target effects.
Click on the links below to learn more about our work in:
- Nuclear Structure and Function
- Cell Cycle, Cancer and Aging
- Genetic and Epigenetic Regulation of Gene Expression
- Musculoskeletal Biology and Pathology
- Stem Cells and Regenerative Medicine
- Cell Signaling and Regulatory Networks
Dicer Deletion increases Bone Mass.
Regulation of Ribosomal RNA in Situ.
Mitotic Retention of Epigenetic Chromatin Marks.
Dobson JR, Taipaleenmäki H, Hu YJ, Hong D, van Wijnen AJ, Stein JL, Stein GS, Lian JB, Pratap J (2014) hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3. Cancer Cell Int 14: 73.
Barutcu AR, Tai PW, Wu H, Gordon JA, Whitfield TW, Dobson JR, Imbalzano AN, Lian JB, van Wijnen AJ, Stein JL, Stein GS (2014) The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter. Nucleic Acids Res 42(16): 10360-72.
Lopez-Camacho C, van Wijnen AJ, Lian JB, Stein JL, Stein GS (2014) Core Binding Factor β (CBFβ) and the Leukemogenic Fusion Protein CBFβ-Smooth Muscle Myosin Heavy Chain (SMMHC) Associate with Mitotic Chromosomes to Epigenetically Regulate Ribosomal Gene Expression. J Cell Biochem in press.
LeBlanc KT, Walcott ME, Gaur T, O'Connell SL, Basil K, Tadiri CP, Mason-Savas A, Silva JA, van Wijnen AJ, Stein JL, Stein GS, Ayers DC, Lian JB, Fanning PJ (2014) Runx1 Activities in Superficial Zone Chondrocytes, Osteoarthritic Chondrocyte Clones and Response to Mechanical Loading. J Cell Physiol in press.
Zhang X, Akech J, Browne G, Russell S, Wixted JJ, Stein JL, Stein GS, Lian JB (2014) Runx2-smad signaling impacts the progression of tumor-induced bone disease. Int J Cancer in press.
Isaac J, Erthal J, Gordon J, Duverger O, Sun HW, Lichtler AC, Stein GS, Lian JB, Morasso MI (2014) DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo. Cell Death Differ 21(9): 1365-76.
Dudakovic A, Camilleri ET, Lewallen EA, McGee-Lawrence ME, Riester SM, Kakar S, Montecino M, Stein GS, Ryoo HM, Dietz AB, Westendorf JJ, van Wijnen AJ (2014) Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells. J Cell Physiol in press.
Chair of the Department of BiochemistryCo-director, Vermont Cancer Center for Basic and Translational Research
Department of Biochemistry
Office: HSRF 326
Lab: HSRF 315
Morgan Czaja, N/A
Mark Fitzgerald, CMB Student
Rodrigo Grandy, Postdoctoral Fellow
Deli Hong, Biochem Grad Student
Cesar Lopez-Camacho, Postdoctoral Fellow
Cesar Lopez-Camacho, Postdoctoral Fellow
Jennifer VanOudenhove, Biochem Grad Student
Hai Wu, Postdoctoral Fellow
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Dr. Hongyu Zhao
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