Differential Response of Human Hepatocyte Chromatin to HDAC Inhibitors as a Function of Microenvironmental Glucose Level

Author(s)

Felisbino, Marina Barreto ^[1] ; da Costa, Thiago Alves ^[1] ; Viccari Gatti, Maria Silvia ^[2] ; Silveira Mello, Maria Luiza ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, R Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut & Bioagents, Campinas, SP - Brazil

• Document type: Journal article
• Source: Journal of Cellular Physiology; v. 231, n. 10, p. 2257-2265, OCT 2016.
• Web of Science Citations: 3

Abstract

Diabetes is a complex multifactorial disorder characterized by chronic hyperglycemia due to impaired insulin secretion. Recent observations suggest that the complexity of the disease cannot be entirely accounted for genetic predisposition and a compelling argument for an epigenetic component is rapidly emerging. The use of histone deacetylase inhibitor (HDACi) in clinical setting is an emerging area of investigation. In this study, we have aimed to understand and compare the response of hepatocyte chromatin to valproic acid (VPA) and trichostatin A (TSA) treatments under normoglycemic or hyperglycemic conditions to expand our knowledge about the consequences of HDACi treatment in a diabetes cell model. Under normoglycemic conditions, these treatments promoted chromatin remodeling, as assessed by image analysis and H3K9ac and H3K9me2 abundance. Simultaneously, H3K9ac marks shifted to the nuclear periphery accompanied by HP1 dissociation from the heterochromatin and a G1 cell cycle arrest. More striking changes in the cell cycle progression and mitotic ratios required drastic treatment. Under hyperglycemic conditions, high glucose per se promoted chromatin changes similar to those promoted by VPA and TSA. Nonetheless, these results were not intensified in cells treated with HDACis under hyperglycemic conditions. Despite the absence of morphological changes being promoted, HDACi treatment seems to confer a physiological meaning, ameliorating the cellular hyperglycemic state through reduction of glucose production. These observations allow us to conclude that the glucose level to which the hepatocytes are subjected affects how chromatin responds to HDACi and their action under high-glucose environment might not reflect on chromatin remodeling. J. Cell. Physiol. 231: 2257-2265, 2016. (c) 2016 Wiley Periodicals, Inc. (AU)

• FAPESP's process: 12/03238-5 - Effects of valproic acid and trichostatin A on chromatin organization and its regulation by epigenetic factors in HepG2 cells grown under hyperglycemic conditions
• Grantee: Marina Barreto Felisbino
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/50015-6 - Chromatin structure and organization with aging and diabetes compared to induced changes in epigenetic markers
• Grantee: Maria Luiza Silveira Mello
• Support Opportunities: Research Projects - Thematic Grants