Histone deacetylase inhibitors (HDACi), including valproic acid (VPA) and trichostatin A (TSA), are known to promote chromatin remodeling in several cell models. Liver is the key organ that releases glucose into the circulation under fasting conditions. An increase in hepatic glucose production due to insulin resistance or insulin deficiency is the central event in the development and progression of diabetes. It is thus of interest to investigate whether the glucose level of the culture medium, which is a fundamental parameter for cell life, would affect the action of VPA and TSA on liver cells. The effect of VPA and TSA treatments on HepG2 cells cultivated under normoglycemic (LG) or hyperglycemic (HG) conditions was investigated to assess changes in the chromatin and epigenetic landscape. Under LG conditions, VPA and TSA treatments promoted global chromatin decondensation, a conclusion that was obtained by image analysis parameters and identification of H3K9ac and H3K9me2 abundance. Moreover, a shift of H3K9ac nuclear localization to the periphery of the nucleus concomitant with disruption of HP1-? from pericentromeric heterochromatin and G1 cell cycle arrest was observed, which might be related to heterochromatin disruption and the spatio-temporal replication properties of different chromatin domains. Regarding the results obtained after HG exposure, some evidences indicated that hyperglycemia per se promotes overall decondensation of the chromatin with loss of repressive histone modifications and increase of activating histone marks. Interestingly, VPA and TSA treatment under HG conditions did not intensify these results. Therefore, chromatin alterations promoted by these drugs under HG in HepG2 cells may be more a function of the different nuclear domains and genes regulated than of global remodeling. These data suggest that the long-held views regarding HDAC inhibition may be subject to more flexibility than previously imagined. Ver menos

Histone deacetylase inhibitors (HDACi), including valproic acid (VPA) and trichostatin A (TSA), are known to promote chromatin remodeling in several cell models. Liver is the key organ that releases glucose into the circulation under fasting conditions. An increase in hepatic glucose production due to insulin resistance or insulin deficiency is the central event in the development and progression of diabetes. It is thus of interest to investigate whether the glucose level of the culture medium, which is a fundamental parameter for cell life, would affect the action of VPA and TSA on liver cells. The effect of VPA and TSA treatments on HepG2 cells cultivated under normoglycemic (LG) or hyperglycemic (HG) conditions was investigated to assess changes in the chromatin and epigenetic landscape. Under LG conditions, VPA and TSA treatments promoted global chromatin decondensation, a conclusion that was obtained by image analysis parameters and identification of H3K9ac and H3K9me2 abundance. Moreover, a shift of H3K9ac nuclear localization to the periphery of the nucleus concomitant with disruption of HP1-α from pericentromeric heterochromatin and G1 cell cycle arrest was observed, which might be related to heterochromatin disruption and the spatio-temporal replication properties of different chromatin domains. Regarding the results obtained after HG exposure, some evidences indicated that hyperglycemia per se promotes overall decondensation of the chromatin with loss of repressive histone modifications and increase of activating histone marks. Interestingly, VPA and TSA treatment under HG conditions did not intensify these results. Therefore, chromatin alterations promoted by these drugs under HG in HepG2 cells may be more a function of the different nuclear domains and genes regulated than of global remodeling. These data suggest that the long-held views regarding HDAC inhibition may be subject to more flexibility than previously imagined. Ver menos