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1.
Dev Biol ; 444 Suppl 1: S193-S201, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098999

RESUMO

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.


Assuntos
Deficiência de Ácido Fólico/fisiopatologia , Crista Neural/metabolismo , Fatores de Transcrição SOXB1/fisiologia , Animais , Embrião de Galinha , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/genética , Repressão Epigenética/genética , Repressão Epigenética/fisiologia , Epigenômica , Receptor 1 de Folato , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histonas/metabolismo , Humanos , Tubo Neural/metabolismo , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/fisiopatologia
2.
Nat Commun ; 14(1): 1617, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36959185

RESUMO

Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5' tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.


Assuntos
Metotrexato , Pequeno RNA não Traduzido , Animais , Masculino , Gravidez , Humanos , Feminino , Metotrexato/efeitos adversos , Metotrexato/metabolismo , Sêmen , Espermatozoides/metabolismo , Ácido Fólico/metabolismo , Pequeno RNA não Traduzido/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo
3.
Front Cell Dev Biol ; 10: 834625, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912103

RESUMO

The neural plate border (NPB) of vertebrate embryos segregates from the neural and epidermal regions, and it is comprised of an intermingled group of multipotent progenitor cells. Folate is the precursor of S-adenosylmethionine, the main methyl donor for DNA methylation, and it is critical for embryonic development, including the specification of progenitors which reside in the NPB. Despite the fact that several intersecting signals involved in the specification and territorial restriction of NPB cells are known, the role of epigenetics, particularly DNA methylation, has been a matter of debate. Here, we examined the temporal and spatial distribution of the methyl source and analyzed the abundance of 5mC/5 hmC and their epigenetic writers throughout the segregation of the neural and NPB territories. Reduced representation bisulfite sequencing (RRBS) on Reduced Folate Carrier 1 (RFC1)-deficient embryos leads to the identification of differentially methylated regions (DMRs). In the RFC1-deficient embryos, we identified several DMRs in the Notch1 locus, and the spatiotemporal expression of Notch1 and its downstream target gene Bmp4 were expanded in the NPB. Cell fate analysis on folate deficient embryos revealed a significant increase in the number of cells coexpressing both neural (SOX2) and NPB (PAX7) markers, which may represent an enhancing effect in the cellular potential of those progenitors. Taken together, our findings propose a model where the RFC1 deficiency drives methylation changes in specific genomic regions that are correlated with a dysregulation of pathways involved in early development such as Notch1 and BMP4 signaling. These changes affect the potency of the progenitors residing in the juncture of the neural plate and NPB territories, thus driving them to a primed state.

4.
Mech Dev ; 154: 24-32, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29654887

RESUMO

The central dogma of molecular biology statically says that the information flows from DNA to messenger RNA to protein. But the recent advances in mass spectrometry and high throughput technology have helped the scientists to view RNA as little more than a courier of genetic information encoded in the DNA. The dynamics of RNA modifications in coding and non-coding RNAs are just emerging as a carrier of non-genetic information, uncovering a new layer of complexity in the regulation of gene expression and protein translation. In this review, we summarize about the current knowledge of N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine (Ψ) modifications in RNA, and described how these RNA modifications are implicated in early animal development and in several human diseases.


Assuntos
RNA/genética , 5-Metilcitosina/metabolismo , Adenosina/análogos & derivados , Adenosina/genética , Animais , Expressão Gênica/genética , Humanos , Pseudouridina/genética
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