Nanos promotes epigenetic reprograming of the germline by down-regulation of the THAP transcription factor LIN-15B

Abstract

Nanos RNA-binding proteins are required for germline development in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of primordial germ cells (PGCs) lacking the nanos homologs nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of transcripts normally expressed in oocytes. We find that this misregulation is due to both delayed turnover of maternal transcripts and inappropriate transcriptional activation. The latter appears to be an indirect consequence of delayed turnover of the maternally-inherited transcription factor LIN-15B, a synMuvB class transcription factor known to antagonize PRC2 activity. PRC2 is required for chromatin reprogramming in the germline, and the transcriptome of PGCs lacking PRC2 resembles that of nos-1nos-2 PGCs. Loss of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These findings suggest that Nanos promotes germ cell fate by downregulating maternal RNAs and proteins that would otherwise interfere with PRC2-dependent reprogramming of PGC chromatin.

Developmental dynamics are a proxy for selective pressures on alternatively polyadenylated isoforms

“…Consistently, we detected expression in late embryogenesis in our miRNA expression data (Fig. 4F and 4H) and interestingly, its profile has a correlation of 0.94 ( P <10 −13 ) with the ratio of the 3’ UTR isoform expression of its target gene F07C6.4 , a gene which is enriched in the germ line, germline precursor cell, the body wall musculature and in the PVD and OLL neurons (Smith et al 2010; Lee et al 2017). Figure 4G shows the distributions of correlation coefficients for dynamically expressed miRNAs with the 3’ UTR isoform expression ratio of their targets in the HCI and LCI groups.…”

TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

“…We nonetheless observed that of the total number of transcription factors found in C. elegans (wTF3.0; Fuxman Bass et al 2016), 389 were present in the list of 7,238 genes that we analyzed by WCA, and 101 of these were identified as contributors (1.5-fold enrichment; p = 6e-06) ( Figure 2C and Table S3). These include genes encoding SMA-3, an R-SMAD in the TGF- signaling pathway, LIN-15B, a THAP transcription factor known to antagonize PRC2 activity (Lee, Lu, and Seydoux 2017), DAF-19, an RXF family transcription factor, 7 CEH homeodomain transcription factors, 22 Nuclear Hormone Receptors (NHRs), and CEBP-1, the worm homologue of mammalian CCAAT/enhancer-binding protein (C/EBP). In all 3 lineages, these genes displayed increased expression between P0 and F2 and a stronger increase in expression between F2 and sterile F4 than between F2 and fertile F4 ( Figure 2D).…”

“…Further analysis suggests that the LIN-15B and CEBP-1 regulatory networks are activated in set-2 mutant germlines, and that this activation is a priming event in loss of germline identity. Ectopic expression of LIN-15B in primordial germ cells (PGC) results in activation of 452 genes (Lee et al, 2017), of which 226 are present in the list of upregulated contributors ( Figure 2E, hypergeometric p-value = 1.71e-93; Table S3).…”

LIN-15B promotes enrichment of H3K9me2 on the promoters of a subset of germline genes that are repressed in somatic cells in C. elegans

“…This scenario has implications for regulation of gene expression in the germ line as well as in the soma. Recent work from the Seydoux lab has further implicated the differential presence of LIN-15B in the germline versus soma in this regulation (Lee et al 2017). Maternally provided LIN-15B is normally removed from the primordial germ cells (PGCs), while DREAM components are not (Lee et al 2017).…”

“…Recent work from the Seydoux lab has further implicated the differential presence of LIN-15B in the germline versus soma in this regulation (Lee et al 2017). Maternally provided LIN-15B is normally removed from the primordial germ cells (PGCs), while DREAM components are not (Lee et al 2017). Our work suggests that loss of LIN-15B from the PGCs may protect essential germline genes from being H3K9 methylated and repressed in those cells.…”