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1.
Epigenetics ; 10(5): 361-72, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25891251

RESUMO

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(ß(Non-exposed) = 0.06, ß(SRI-exposed) = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status--both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)--was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight.


Assuntos
Antidepressivos/efeitos adversos , Citocromo P-450 CYP2E1/metabolismo , Metilação de DNA/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Adulto , Estudos de Coortes , Ilhas de CpG , Feminino , Humanos , Recém-Nascido , Leucócitos/efeitos dos fármacos , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Parto/efeitos dos fármacos , Gravidez , Cordão Umbilical/citologia , Cordão Umbilical/efeitos dos fármacos
2.
Brain ; 136(Pt 10): 3018-27, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24030951

RESUMO

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Metilação de DNA/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , DNA/genética , Epigênese Genética/genética , Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética
3.
PLoS One ; 7(9): e45592, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23049819

RESUMO

In humans, naturally acquired microchimerism has been observed in many tissues and organs. Fetal microchimerism, however, has not been investigated in the human brain. Microchimerism of fetal as well as maternal origin has recently been reported in the mouse brain. In this study, we quantified male DNA in the human female brain as a marker for microchimerism of fetal origin (i.e. acquisition of male DNA by a woman while bearing a male fetus). Targeting the Y-chromosome-specific DYS14 gene, we performed real-time quantitative PCR in autopsied brain from women without clinical or pathologic evidence of neurologic disease (n=26), or women who had Alzheimer's disease (n=33). We report that 63% of the females (37 of 59) tested harbored male microchimerism in the brain. Male microchimerism was present in multiple brain regions. Results also suggested lower prevalence (p=0.03) and concentration (p=0.06) of male microchimerism in the brains of women with Alzheimer's disease than the brains of women without neurologic disease. In conclusion, male microchimerism is frequent and widely distributed in the human female brain.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Quimerismo , Troca Materno-Fetal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Autopsia , Encéfalo/patologia , Cromossomos Humanos Y , Feminino , Feto , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Reação em Cadeia da Polimerase em Tempo Real
4.
Biotechniques ; 52(6): 381-5, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22668417

RESUMO

Efficient isolation of specific, intact, living neurons from the adult brain is problematic due to the complex nature of the extracellular matrix consolidating the neuronal network. Here, we present significant improvements to the protocol for isolation of pure populations of neurons from mature postnatal mouse brain using fluorescence activated cell sorting (FACS). The 10-fold increase in cell yield enables cell-specific transcriptome analysis by protocols such as nanoCAGE and RNA seq.


Assuntos
Encéfalo/citologia , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo/métodos , Neurônios/citologia , Trealose/química , Animais , Camundongos , Camundongos Transgênicos , RNA Mensageiro/isolamento & purificação , Transcriptoma , Trealose/farmacologia
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