Histone deacetylase 7 (HDAC7), a Class IIa HDAC, is an essential player in animal development. This protein primarily functions as a transcriptional corepressor of a diverse set of transcription factors. The transcriptional activity of HDAC7 has been shown to be modulated by nucleocytoplasmic shuttling. Nevertheless, the mechanisms underlying the regulation and functions of HDAC7 still remain unclear.
CRM1, 14-3-3 proteins, and CaMK play important roles in the trafficking of HDAC7, but the interplay between these proteins in this process is not clearly understood. We show that CRM1 is capable of promoting the cytoplasmic localization of HDAC7 independent of phosphorylation and 14-3-3 binding. Furthermore, our work also identified a novel regulatory mechanism in which HDAC7 can be recruited to distinct subnuclear domains, promyelocytic leukemia protein (PML) nuclear bodies (NBs). We show here that endogenous HDAC7 and PML interact and partially co-localize in PML NBs. Tumor necrosis factor alpha (TNFα) treatment of human umbilical vein endothelial cells (HUVECs) results in the recruitment of HDAC7 to PML NBs and the enhanced association between HDAC7 and PML. We show that by sequestration HDAC7, PML activates HDAC7 target gene, including Matrix Metalloprotease-10 (MMP-10). These results reveal a novel mechanism in which PML blocks the association between HDAC7 and MEF2s by keeping HDAC7 in subnuclear domains.
In addition to its role in transcriptional regulation, we explored other potential functions of HDAC7. We show that HDAC7 knockdown reduces the size and the number of the PML NBs in HUVECs. Moreover, HDAC7 stimulates PML sumoylation in vivo and in vitro, suggesting that it possesses a SUMO E3 ligase-like activity. Importantly, HDAC7 knockdown abrogates TNFα-induced PML sumoylation and formation of PML NBs in HUVECs. These results demonstrate a novel function of HDAC7 and provide a regulatory mechanism of PML sumoylation. Lastly, we examined the role of HDAC7 in muscle differentiation. Our work demonstrates that HDAC7 shuttles between the nucleus and the cytoplasm during muscle differentiation. We further demonstrated that constitutive nuclear localization of HDAC7 impairs myogenesis. These results may provide a molecular basis for the development of the potential therapeutic approaches for the treatment of heart and muscular diseases.