Histone deacetylase 7 and its interacting proteins in endothelial cells

Case Western Reserve University, Cleveland OH

Investigators

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Abstract

DESCRIPTION (provided by applicant): HDAC7 is a member of the class IIa HDACs that associate with transcription factors including myocyte factor 2 (MEF2) to repress expression of target genes. We show that HDAC7 interacts with PML (promyelocytic leukemia protein). Recent studies in mice have demonstrated a critical role for HDAC7 and PML in the normal development of endothelial cells (ECs). The relationship between HDAC7 and PML is complex. Of primary importance is that the binding of HDAC7 to PML leads to derepression of HDAC7 target genes with clear biological consequences such as altered expression of HDAC7 target genes in the case of endothelial cells. The interaction of HDAC7 and PML also controls the level of PML sumoylation and PML NB formation. All of these effects will be investigated at the mechanistic level with a focus on endothelial cells and their responses to inflammatory stimuli. The specific aims are: 1) To elucidate the mechanisms underlying TNF1-induced accumulation of PML mRNA and protein levels. We will employ chemical inhibitors, siRNA, and dominant-negative expression strategies to delineate the mechanisms controlling TNF1-induced accumulation of PML mRNA, protein levels, PML sumoylation, and formation of PML NBs. 2) To investigate the mechanisms by which HDAC7 mediates TNF1-induced MCP-1 transcription. We hypothesize that TNF1-induced formation of PML NBs sequesters HDAC7, leading to derepression of MMP-10 and MCP-1, both of which are targets of HDAC7. We will test our model using chromatin immunoprecipitation (ChIP), knockdown by siRNA, and transient transfection reporter assays to characterize the MCP-1 promoter. We are also interested in determining whether changes in the histone modifications occur at the MCP-1 promoter upon TNF1 treatment. We will simultane3) To dissect the role of PML and TNF1 in ECs. We will dissect the roles of PML in TNF1-mediated adhesion, migration, proliferation, apoptosis, and remodeling of blood vessels using in vitro and in vivo approaches. In summary, our proposed study is aimed at dissecting the mechanisms and identifying the effectors in cytokine-mediated EC activation. Understanding the pathways that control inflammation, proliferation, apoptosis, and angiogenesis may have therapeutic implications for treating vascular diseases.