A Novel Role for DNA Hydroxymethylation in Sexual Differentiation of the Mouse Brain

• Autores: Cisternas, Carla Daniela; Cortes, Laura R.; Forger, Nancy G.
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: documento de conferencia
• Materia: Testosterone; Hydroxymethylation; Sexual differentiation; Tet enzymes
• Institución: Universidad Nacional de Córdoba

Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.
Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.
Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.
Fil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.
Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.
Many sex differences in the brain are differences in neuronal phenotype (i.e., number of cells expressing a specific neurochemical marker). Epigenetic modifications, such as DNA methylation, control the development of cell phenotype throughout the body during embryogenesis, and sex differences in neurochemical cell phenotype could be due to differences in the control of DNA methylation. To test this, we first inhibited DNA methylation in the brains of newborn mice during the critical period of sexual differentiation. We found sex-specific effects (the inhibition of DNA methylation increased the number of calbindin-expressing cells only in females, and the number of estrogen receptor alpha cells only in males). As a result, sex differences were reduced or eliminated in the treated groups. We next hypothesized that DNA methylation during development depends on a balance between the addition of methyl groups (by DNA methyltransferases, DNMTs), and their removal (by ten-eleven translocases, Tets). Tet enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine. This is a first step to removal of the methyl mark, but hydroxymethylation is also emerging as a stable epigenetic mark in its own right, especially in the brain where it is found at much higher levels than in other tissues. We find that both DNMTs and Tets are expressed at even higher levels in the neonatal brain than at later ages, and that sex differences in expression are found only during the first postnatal week. Males have greater expression of Tet2 and Tet3 and lower expression of Dnmt1 in the preoptic area of the hypothalamus and this is associated with less 5mC in the same region. We are currently examining the effects of a transient downregulation in Tet enzymes to test for a causal relationship between Tet enzyme expression and sex differences in neuronal phenotype. Overall, our results suggest the novel idea that DNA de-methylation may primarily drive sex differences early in brain developmentFunding: This study was funded by a seed grant from the Brains & Behavior Program at Georgia State University.
Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.
Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.
Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.
Fil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.
Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.
Bioquímica y Biología Molecular (ídem 3.1.10)