Abstract
BackgroundIn order to prepare the genome for gametogenesis, primordial germ cells (PGCs) undergo extensive epigenetic reprogramming during migration toward the gonads in mammalian embryos. This includes changes on a genome-wide scale and additionally in females the remodeling of the inactive X-chromosome to enable X-chromosome reactivation (XCR). However, if global remodeling and X-chromosomal remodeling are related, how they occur in PGCs in vivo in relation to their migration progress and which factors are important are unknown.ResultsHere we identify the germ cell determinant PR-domain containing protein 14 (PRDM14) as the first known factor that is instrumental for both global reprogramming and X-chromosomal reprogramming in migrating mouse PGCs. We find that global upregulation of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark is PRDM14 dosage dependent in PGCs of both sexes. When focusing on XCR, we observed that PRDM14 is required for removal of H3K27me3 from the inactive X-chromosome, which, in contrast to global upregulation, takes place progressively along the PGC migration path. Furthermore, we show that global and X-chromosomal reprogramming of H3K27me3 are functionally separable, despite their common regulation by PRDM14.ConclusionsIn summary, here we provide new insight and spatiotemporal resolution to the progression and regulation of epigenome remodeling along mouse PGC migration in vivo and link epigenetic reprogramming to its developmental context.
Highlights
In order to prepare the genome for gametogenesis, primordial germ cells (PGCs) undergo extensive epigenetic reprogramming during migration toward the gonads in mammalian embryos
PR-domain containing protein 14 (PRDM14) controls number and local distribution of PGCs during their migration To address the function of PRDM14 for PGC number and migration, we immunostained whole mount embryonic day (E)9.5 mouse embryos from Prdm14+/− x Prdm14+/− heterozygous crosses for AP2γ, a specific marker and critical factor for PGC development [21, 28]
We found that migrating PGCs at this stage were spread throughout the hindgut and observed in Prdm14−/− embryos a strong depletion of PGCs or even their absence (9/22 embryos), when compared to wild type and heterozygous littermates (Fig. 1a, Additional file 1: Fig. S1, Additional file 2: Table S1), which is consistent with a previous study of this mouse line [20]
Summary
In order to prepare the genome for gametogenesis, primordial germ cells (PGCs) undergo extensive epigenetic reprogramming during migration toward the gonads in mammalian embryos. This includes changes on a genome-wide scale and in females the remodeling of the inactive X-chromosome to enable X-chromosome reactivation (XCR). [8, 9, 11, 14, 15], the molecular mechanisms and factors, which are functionally important to reverse the inactive X-chromosome state, are largely unknown Identifying such X-reactivation factors would be a key step toward revealing mechanistically how epigenetic memory can be erased in the germ line. In the absence of PRDM14, downregulation of Xist and removal of the H3K27me mark from the inactive X-chromosome are perturbed, likely due to repressive functions of PRDM14 on Xist and its activator Rnf12/Rlim [16, 18]
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