File:FMR1 gene silencing.jpg

The timing of FMR1 gene silencing during development

Fragile X syndrome (FXS) results from full mutations (FMs) which are exclusively transmitted by mothers in their unmethylated form (uFM).

Hypermethylation is first established stochastically before/at the time of embryo implantation. This occurs in the inner cell mass (ICM, naïve cells) or the epiblast (primed cells) of affected fetuses, during the developmental stages when embryonic stem cell lines are established.

FM alleles remain unmethylated in primordial germ cells (PGCs) precursors, and extra-embryonic tissues.

Post-implantation to 10 week fetuses - Later during development, a second wave of de novo methylation takes place.

Fetuses 10–13 weeks - Hypermethylation coincides with a selection against cells with an uFM, and results in FMR1 gene silencing in the majority of fetal tissues and in the soma of FXS affected individuals.

PGCs initiate differentiation - experience a third wave of de novo methylation in the male germ line. FM alleles become methylated (spermatogonia) and, as a result are eliminated. Otherwise they contract, resulting in the exclusive production of mature sperm cells with alleles in the premutation (PM) range (mature sperm).

This is different from the female germ line, where FMs remain unmethylated, awaiting the time of fertilization.

TE, Trophectoderm; PE, primitive endoderm. (text modified from original figure legend)

Links: Fragile X Syndrome

Reference

Mor-Shaked H & Eiges R. (2018). Reevaluation ofFMR1Hypermethylation Timing in Fragile X Syndrome. Front Mol Neurosci , 11, 31. PMID: 29467618 DOI.

Copyright

© 2018 Mor-Shaked and Eiges. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Figure 1. Modified in size and Reference PMID added to original figure.