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Action of valproic acid on chromatin structure and function


The action of Valproic Acid (VPA), a histone deacetylase inhibitor, has been investigated in several cell models under various experimental conditions. VPA has also been considered for clinical applications because of its modulating activity on gene expression. VPA affects different types of epigenetic marks through mechanisms that vary, depending on cell types and their physiological/pathological conditions, and which are not fully understood. Described VPA action mechanisms involve interference on levels of histone acetylation with predominance of induction of H3K9 and H4K8 acetylation, DNA demethylation and histone methylation and/or demethylation. Present proposal aims to bring contribution on how different metabolic pathways of the VPA action express at chromatin structural and functional levels in some cell types. The issues addressed are the following: 1. What changes are promoted by VPA at the H3K9/14 acetylation levels that could reflect on differential gene expression in certain genetic pathways of interest in a liver cell model under hyperglycemic microenvironment? 2. What is the level of DNA methylation that is affected by VPA in cells where this drug inhibits histone deacetylases and promotes H3K9 and H4K8 acetylation and chromatin remodeling, and how this phenomenon works (passive or active via)? 3. By what mechanism VPA allows unraveling of heterochromatic bodies without involvement of H3K9 and H4K8 acetylation? The methodology will involve ChIP-seq and RNA-seq assays, immunoassays, bioinformatics, image analysis, flow cytometry, confocal microscopy, laser microsurgery and infrared microspectroscopy. (AU)

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Scientific publications (12)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
IMPERADOR, CARLOS HENRIQUE L.; RODRIGUES, VERA L. C. C.; MELLO, MARIA LUIZA S.. The Topological Distribution of the Chromocenter in Panstrongylus megistus (Burmeister) Malpighian Tubule Cells Examined by Confocal Microscopy. CYTOLOGIA, v. 86, n. 1, p. 47-54, . (15/10356-2)
VIDAL, BENEDICTO DE CAMPOS; MELLO, MARIA LUIZA S.. Sodium valproate (VPA) interactions with DNA and histones. International Journal of Biological Macromolecules, v. 163, p. 219-231, . (15/10356-2)
IMPERADOR, CARLOS HENRIQUE L.; BARDELLA, VANESSA B.; DOS ANJOS, ELI HEBER M.; RODRIGUES, VERA L. C. C.; CABRAL-DE-MELLO, DIOGO C.; MELLO, MARIA LUIZA S.. Spatial Distribution of Heterochromatin Bodies in the Nuclei ofTriatoma infestans(Klug). Microscopy and Microanalysis, v. 26, n. 3, p. 567-574, . (15/10356-2)
BASSANI, ALESSANDRA; ROCHA, MARINA AMORIM; RODRIGUES, VERA LUCIA C. C.; SANTOS, DOUGLAS S.; NASCIMENTO, JULIANA DAMIELI; DA ROSA, JOAO ARISTEU; MELLO, MARIA LUIZA S.. Effects of sodium valproate on the chromatin of Triatoma infestans (Klug, 1834) (Hemiptera, Reduviidae) under in vitro culture conditions. ACTA HISTOCHEMICA, v. 123, n. 3, . (18/07888-0, 15/10356-2)
ROCHA, MARINA AMORIM; BREDA VERONEZI, GIOVANA MARIA; FELISBINO, MARINA BARRETO; VICCARI GATTI, MARIA SILVIA; TAMASHIRO, WIRLA M. S. C.; SILVEIRA MELLO, MARIA LUIZA. Sodium valproate and 5-aza-2 `-deoxycytidine differentially modulate DNA demethylation in G1 phase-arrested and proliferative HeLa cells. SCIENTIFIC REPORTS, v. 9, . (14/23842-0, 15/10356-2)
MELLO, MARIA LUIZA S.. Sodium Valproate-Induced Chromatin Remodeling. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, . (15/10356-2)
FELISBINO, MARINA BARRETO; ZIEMANN, MARK; KHURANA, ISHANT; OKABE, JUN; AL-HASANI, KEITH; MAXWELL, SCOTT; HARIKRISHNAN, K. N.; MARTINS DE OLIVEIRA, CAMILA BORGES; MELLO, MARIA LUIZA S.; EL-OSTA, ASSAM. Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways. SCIENTIFIC REPORTS, v. 11, n. 1, . (14/10198-5, 10/50015-6, 15/10356-2)
D. S. SANTOS; M. A. ROCHA; M. L. S. MELLO. Estudos epigenéticos em insetos e a perspectiva do ácido valpróico. Brazilian Journal of Biology, v. 84, . (15/10356-2, 18/07888-0, 19/20833-3)
ALVARENGA, ELENICE M.; IMPERADOR, CARLOS H. L.; BARDELLA, VANESSA B.; RODRIGUES, VERA L. C. C.; MONDIN, MATEUS; CABRAL-DE-MELLO, DIOGO C.; MORAES, ALBERTO S.; MELLO, MARIA LUIZA S.. Histone acetylation and methylation marks in chromatin of Panstrongylus megistus (Hemiptera, Reduviidae). ACTA HISTOCHEMICA, v. 120, n. 6, p. 572-577, . (10/50015-6, 15/10356-2)
VIDAL, BENEDICTO DE CAMPOS; MELLO, MARIA LUIZA S.. Chiral supramolecular order revealed during the formation of calf thymus and phage DNA crystals. Micron, v. 102, p. 44-50, . (15/10356-2)
MELLO, MARIA LUIZA S.; VIDAL, BENEDICTO DE CAMPOS. The Feulgen reaction: A brief review and new perspectives. ACTA HISTOCHEMICA, v. 119, n. 6, p. 603-609, . (15/10356-2)
VIDAL, BENEDICTO DE CAMPOS; MELLO, MARIA LUIZA S.. Toluidine blue staining for cell and tissue biology applications. ACTA HISTOCHEMICA, v. 121, n. 2, p. 101-112, . (15/10356-2)

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