Artículo
Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube
Alata Jimenez, Nagif
; Torres Pérez, Sergio Andres; Sanchez Vasquez, Estefania
; Fernandino, Juan Ignacio
; Strobl Mazulla, Pablo Hernan
Fecha de publicación:
12/2018
Editorial:
Academic Press Inc Elsevier Science
Revista:
Developmental Biology
ISSN:
0012-1606
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Folate deficiency has been known to contribute to neural tube and neural crest defects, but why these tissues are particularly affected, and which are the molecular mechanisms involved in those abnormalities are important human health questions that remain unanswered. Here we study the function of two of the main folate transporters, FolR1 and Rfc1, which are robustly expressed in these tissues. Folate is the precursor of S-adenosylmethionine, which is the main donor for DNA, protein and RNA methylation. Our results show that knockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, two epigenetic modifications that play an important role during neural and neural crest development. Additionally, by knocking down folate transporter or pharmacologically inhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neural crest markers in the dorsal neural tube. This is correlated with neural crest associated defects, with particular impact on orofacial formation. By using bisulfite sequencing, we show that this phenotype is consequence of reduced DNA methylation on the Sox2 locus at the dorsal neural tube, which can be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance of folate as a source of the methyl groups necessary for the establishment of the correct epigenetic marks during neural and neural crest fate-restriction.
Palabras clave:
Dna Methylation
,
Epigenetic
,
Folate
,
Neural Crest
,
Sox2
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(CCT - LA PLATA)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - LA PLATA
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - LA PLATA
Articulos(IIB-INTECH)
Articulos de INST.DE INVEST.BIOTECNOLOGICAS - INSTITUTO TECNOLOGICO CHASCOMUS
Articulos de INST.DE INVEST.BIOTECNOLOGICAS - INSTITUTO TECNOLOGICO CHASCOMUS
Citación
Alata Jimenez, Nagif; Torres Pérez, Sergio Andres; Sanchez Vasquez, Estefania; Fernandino, Juan Ignacio; Strobl Mazulla, Pablo Hernan; Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube; Academic Press Inc Elsevier Science; Developmental Biology; 444; Supl. 1; 12-2018; 193-201
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