Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube

SÁNCHEZ-VÁSQUEZ, ESTEFANÍA; ALATA JIMENEZ, NAGIF; FERNANDINO, JUAN I.; TORRES PÉREZ, SERGIO A.; STROBL-MAZZULLA, PABLO H.

DEVELOPMENTAL BIOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2018 vol. 444 p. 193 - 201

0012-1606

Folate deficiency has been known to contribute to neural tube and neuralcrest defects, but why these tissues are particularly affected, and which arethe molecular mechanisms involved in those abnormalities are important humanhealth questions that remain unanswered. Here we study the function of two ofthe main folate transporters, FolR1and Rfc1, which are robustly expressedin these tissues. Folate is the precursor of S-adenosylmethionine, which is themain donor for DNA, protein and RNA methylation. Our results show thatknockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, twoepigenetic modifications that play an important role during neural and neuralcrest development. Additionally, by knocking down folate transporter or pharmacologicallyinhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neuralcrest markers in the dorsal neural tube. This is correlated with neural crestassociated defects, with particular impact on orofacial formation. By usingbisulfite sequencing, we show that this phenotype is consequence of reduced DNAmethylation on the Sox2 locus at the dorsal neural tube, whichcan be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance offolate as a source of the methyl groups necessary for the establishment of thecorrect epigenetic marks during neural and neural crest fate-restriction.