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The research interests of our laboratory center on chromatin modifications and its impact on regulation of gene expression and nuclear structure, particularly as it relates changes associated with malignant transformation. Clearly, the interplay between activation and repression of transcription that imposes normal transcriptional control becomes disrupted in cancer. Besides their roles in promoter-specific transcriptional regulation, histone modifiers also play a role in the establishment of large chromosomal domains, and therefore function in maintenance of chromosomal integrity. We and others have shown that deregulation of histone modifying complexes, including Histone Deacetylases (HDACs)-containing complexes, participate to the oncogenic transformation in numerous human cancers. Several studies suggested that blocking the enzymatic activity of HDAC complexes (e.g., using histone deacetylase inhibitors) could prevent tumorigenesis and selectively induce cell death in transformed cells. While HDACs are integral components of several gene regulatory complexes, HDAC inhibitors developed to date exhibit little or no specificity towards individual HDAC-containing complex. Thus, the identification of pathways involved in the modulation of the activities of specific HDAC complexes is a priority in cancer therapy. Knowledge of these control mechanisms in both normal physiology and malignancy is essential for the better understanding of the malignant process that will allow development of novel therapeutic and diagnostic approaches to human disease.
We have recently developed valuable biological tools to study the prominent HDAC-containing complex in mammalian cells, the mSin3-HDAC complex. The mSin3 complex was the first chromatin modifying complex shown to be deregulated in human cancers. However, the molecular basis for the malignant phenotype in those tumors remain unclear, impairing the development of efficient targeted therapies. Using genetic recombination, we generated mouse strains that can be spatially and temporally genetically inactivated for different components of the mSin3-HDAC complex. Those unique reagents will enable the precise delineation of the in vivo consequences of deregulation or inactivation of the complex on mammalian development and oncogenesis, and enable the development of rational targeted therapies.
Senescence Phenotypes Induced by Ras in Primary Cells
Lau, Lena; David, Gregory. Senescence Phenotypes Induced by Ras in Primary Cells. Methods in molecular biology. 2017 ;1534:17-30 (2297462)
The chromatin associated Phf12 protein maintains nucleolar integrity and prevents premature cellular senescence
Graveline, Richard; Marcinkiewicz, Katarzyna; Choi, Seyun; Paquet, Marilene; Wurst, Wolfgang; Floss, Thomas; David, Gregory. The chromatin associated Phf12 protein maintains nucleolar integrity and prevents premature cellular senescence. Molecular & cellular biology. 2016 Dec 12;:?-? (2363372)
URI Regulates KAP1 Phosphorylation and Transcriptional Repression Via PP2A Phosphatase in Prostate Cancer Cells
Mita, Paolo; Savas, Jeffrey N; Briggs, Erica M; Ha, Susan; Gnanakkan, Veena; Yates, John R 3rd; Robins, Diane M; David, Gregory; Boeke, Jef D; Garabedian, Michael J; Logan, Susan K. URI Regulates KAP1 Phosphorylation and Transcriptional Repression Via PP2A Phosphatase in Prostate Cancer Cells. Journal of biological chemistry. 2016 Dec 02;291(49):25516-25528 (2288712)
The chromatin associated Sin3B protein is required for hematopoietic stem cell functions in mice
Cantor, David J; David, Gregory. The chromatin associated Sin3B protein is required for hematopoietic stem cell functions in mice. Blood. 2016 Nov 2;129(1):60-70 (2297312)
Emerging Roles of Epigenetic Regulator Sin3 in Cancer
Bansal, N; David, G; Farias, E; Waxman, S. Emerging Roles of Epigenetic Regulator Sin3 in Cancer. Advances in cancer research. 2016 ;130:113-135 (2059442)