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| Author(s): |
Marina Barreto Felisbino
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2016-05-08 |
| Examining board members: |
Maria Luiza Silveira Mello;
Marcelo Emilio Beletti;
Patricia Pasquali Parise Maltempi;
Murilo Vieira Geraldo;
Shirlei Maria Recco Pimentel
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| Advisor: | Maria Luiza Silveira Mello |
| Abstract | |
Diabetes is a complex disorder involving several factors in its progression, among which those related with epigenetics control. A potential strategy to reverse epigenetic alterations associated with diseases is the use of histone deacetylase inhibitors (HDACis). HDACis, like valproic acid (VPA) and trichostatin A (TSA) have been reported to induce plasmatic glucose reduction, mitigation of insulin resistance and decrease in microvascular late complications, as well as involvement in gluconeogenesis control. Furthermore, HDACis have been revealed as potential immunomodulatory agents, because they are capable of reducing the severity of inflammatory and autoimmune diseases. Given that the liver is a fundamental organ for lipid and glucose metabolism, this study was developed in the HepG2 hepatocyte cells model. Chromatin structure alterations associated with epigenetic and gene expression changes were evaluated aiming to understand the large-scale consequences of hyperglycemia, and the HDACi action on this context. VPA and TSA treatments in HepG2 cells under normoglycemia promoted chromatin remodeling as assessed by image analysis and evaluation of H3K9ac and H3K9me2 abundance. Simultaneously, H3K9ac marks were found to shift to the nuclear periphery accompanied by HP1 dissociation from the heterochromatin and G1 cell cycle arrest. High glucose per se promoted chromatin and epigenetic changes similar to those described above. Interestingly, these results were not intensified in cells treated with HDACis under hyperglycemic conditions. Nonetheless, despite the absence of morphological changes being promoted, HDACi treatment seems to confer a physiological meaning, through reduction of glucose production. These observations allow us to conclude that the microenvironmental glucose level affects how chromatin responds to HDACis and their action may be more concerned with chromatin domains affected and differently regulated genes not reflecting on global chromatin remodeling. A genome-wide analysis of a multitude of genes potentially influenced by VPA was attempted through RNA-seq, aiming to understand its mechanisms of action on amelioration of the hyperglycemic state. Initial bioinformatics analysis has associated VPA action with complement and coagulation gene modulation. Indeed, complement and coagulation pathways have common evolutionary origins and understanding the crosstalk between these pathways has fundamental clinical implications in the context of inflammatory diseases. The transcription factor network controlling gene expression may be the connecting point between immune system and metabolic pathways and further investigation of these gene regulators as well of the acetylation pattern of gene promoters may better complement present conclusions. Until this moment, the hyperglycemia influence on chromatin texture and epigenetic regulation, as well as unraveling of a new mechanism of mitigation of hyperglycemia have been evaluated to be promoted by VPA, which might improve the therapeutic approaches for diabetes (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 |