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TEX15 Associates with MILI and Silences Transposable Elements in Male Germ Cells

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TEX15 Associates with MILI and Silences Transposable Elements in Male Germ Cells Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION noncatalytic germ cell-specific paralog of DNMT3A/3B, TEX15 associates with MILI causes reactivation of TEs in male germ cells and loss and silences transposable of maternal genomic imprints, resulting in sterility (Bourc’his et al. 2001; Bourc’his and Bestor 2004). Loss of elements in male germ cells DNMT3C, a rodent and germ cell-specific de novo DNA methyltransferase, leads to reactivation of LINE1 and Fang Yang,1 Yemin Lan,2 Radha Raman Pandey,3 3 2 IAP retrotransposons (Barau et al. 2016). In addition to David Homolka, Shelley L. Berger, DNA methylation, repressive histone modifications Ramesh S. Pillai,3 Marisa S. Bartolomei,2 (H3K9me2 and H3K9me3) are important for silencing of and P. Jeremy Wang1 transposable elements (Di Giacomo et al. 2013; Liu et al. 2014; Pezic et al. 2014; Zamudio et al. 2015). 1Department of Biomedical Sciences, University of Pennsylvania The piRNA (Piwi-associated small noncoding RNAs) School of Veterinary Medicine, Philadelphia, Pennsylvania pathway is an evolutionarily conserved RNA-based TE si- 19104, USA; 2Epigenetics Institute, Department of Cell and lencing mechanism in the germline (Siomi et al. 2011). Developmental Biology, Perelman School of Medicine, piRNAs are mostly derived from TEs in early germ cells University of Pennsylvania, Philadelphia, Pennsylvania 19104, (Aravin et al. 2008; Kuramochi-Miyagawa et al. 2010). Ge- USA; 3Department of Molecular Biology, Science III, University nome-wide demethylation in primordial germ cells of Geneva, CH-1211 Geneva 4, Switzerland (PGCs) causes a burst of TE expression (Bourc’his and Bes- tor 2004). During PGC epigenetic reprogramming, the DNA methylation is a major silencing mechanism of piRNA pathway is activated and the increased expression transposable elements (TEs). Here we report that of TE transcripts drives piRNA production, which serve TEX15, a testis-specific protein, is required for TE silenc- two purposes (Aravin et al. 2008). First, piRNAs direct ing. TEX15 is expressed in embryonic germ cells and func- Piwi proteins to specifically cleave TE transcripts to en- tions during genome-wide epigenetic reprogramming. force posttranscriptional silencing. Second, piRNAs de- The Tex15 mutant exhibits DNA hypomethylation in rived from activated TEs instruct de novo methylation TEs at a level similar to Mili and Dnmt3c but not Miwi2 of TE promoters, thereby establishing transcriptional si- mutants. TEX15 is associated with MILI in testis. As lencing through a mechanism that is yet to be completely loss of Tex15 causes TE desilencing with intact piRNA elucidated in mammals. production, our results identify TEX15 as a new essential Our previous cDNA subtraction genomic screen identi- fied 36 germ cell-specific genes from mouse spermatogo- epigenetic regulator that may function as a nuclear effec- nia (Wang et al. 2001). Five genes from this genomic tor of MILI to silence TEs by DNA methylation. screen (Mili, Vasa, Tdrd1, Mov10l1, and Rnf17) were sub- Supplemental material is available for this article. sequently found to encode key protein components of the piRNA pathway. MOV10L1, a bona fide RNA helicase, Received November 27, 2019; revised version accepted forms a complex with MILI (PIWIL2) and TDRD1, binds April 3, 2020. specifically to piRNA precursors to initiate piRNA bio- genesis, and is required for silencing retrotransposons in male germ cells (Zheng et al. 2010; Vourekas et al. Transposable elements (TEs), including LINEs, SINEs, 2015). The hallmarks of most piRNA pathway mouse mu- and endogenous retroviruses, occupy ∼40% of the mam- tants are activation of TEs in germ cells, meiotic arrest, malian genome (Goodier and Kazazian 2008). Retrotrans- and male sterility. Notably, Tex15 (testis-specific gene posons amplify in the genome by a “copy and paste” 15) was also first identified in this genomic screen mechanism and retrotransposition of TE sequences into (Wang et al. 2001). TEX15 is a large protein of 3059 resi- new genomic sites can change the expression level or pat- dues with no known domain or binding partner. As previ- − − tern of neighboring genes or generate new genes. While ously reported, the Tex15 / males are sterile due to TEs play an important role in genome evolution at the meiotic arrest but females are fertile (Yang et al. 2008). − − species level, integration of TEs can potentially disrupt Tex15 / spermatocytes exhibit a failure in chromosomal the function of targeted genes and thus be deleterious at synapsis and meiotic recombination (Yang et al. 2008). − − the individual level. Indeed, TEs are culprits in >60 human Because the Tex15 / mice mimic mouse mutants with genetic diseases (Goodier and Kazazian 2008). desilencing of TEs, we asked whether TEs are desilenced − − Given the dramatic impact of TEs on genome integrity, in male germ cells from Tex15 / mice. In addition, muta- cells have evolved multiple robust silencing mechanisms. tions in human TEX15 cause infertility and meiotic arrest DNA methylation is the major silencing mechanism for in men (Okutman et al. 2015). Here we report that TEX15 TEs in mammals (Bourc’his and Bestor 2004). Mainte- associates with MILI and is a new and essential factor in nance (DNMT1) and de novo (DNMT3A and DNMT3B) the epigenetic silencing of TEs in male germ cells. DNA methyltransferases are required for methylation of IAP (intracisternal A particle) retrotransposons (Walsh et al. 1998; Kato et al. 2007). Inactivation of DNMT3L, a © 2020 Yang et al. This article is distributed exclusively by Cold Spring [Keywords: DNA methylation; epigenetics; MILI; spermatogenesis; Harbor Laboratory Press for the first six months after the full-issue publi- TEX15; transposable element] cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (Attribu- Article published online ahead of print. Article and publication date are tion-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.335489.119. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 34:745–750 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 745 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Yang et al. Results and Discussion sults show that TEX15 is required for silencing of both LINE1 and IAP retrotransposons in male embryonic TEX15 represses evolutionarily young transposable germ cells. elements in embryonic male germ cells Shortly after sex determination, embryonic male germ cells cease dividing and undergo genome-wide epigenetic We examined the expression of Tex15 in perinatal male reprogramming, which includes genome-wide de novo germ cells. RNA-seq analysis showed that Tex15 tran- DNA methylation and establishment of paternal imprint- script abundance was high at embryonic day 16.5 (E16.5) ing (Hackett et al. 2012). At E16.5, genome methylation and E18.5 and increased at postnatal day 2.5 (P2.5). In con- levels in male germ cells are low, become higher at trast, Mili (Piwil2) and Miwi2 (Piwil4) levels were high at E18.5, and at postnatal day 2.5 (P2.5), genome-wide de E16.5 and decreased at P2.5 (Supplemental Fig. S1A). By novo methylation is largely complete. To systematically immunofluorescence, we found that TEX15 protein local- profile TE expression, we performed RNA-seq analysis ized to both nucleus and cytoplasm in embryonic male − − − of FACS-sorted Tex15 / and Tex15+/ male germ cells germ cells—gonocytes at E17.5 (Fig. 1A). The TEX15 lo- at E16.5, E18.5, and P2.5 (Fig. 1D; Supplemental Table calization signal was specific, as it was absent in the − − S1). Germ cells were sorted from Oct4-GFP-positive tes- Tex15 / germ cells (Fig. 1A). The expression in embryon- tes. Three biological replicates were performed per geno- ic testis suggests a functional role for TEX15 in early germ type per time point. Two-thousand to 6000 germ cells cells. − − from each embryo or pup were used per RNA-seq library. Tex15 / male mice were sterile with meiotic arrest, At E16.5, most TE families exhibited less than twofold while females were fertile (Yang et al. 2008). We noticed − − change in Tex15 / germ cells, although a few ERVK fam- the presence of a unique class of spermatocytes with en- ilies (IAPLTR4_I, IAPLTR1_Mm, IAPEz-Int) and one larged nuclei and loose chromatin (Yang et al. 2008), a phe- ERV1 family (RLTR4_MM-int) were up-regulated by notype commonly observed in mutant testes, such as −/− − − − − greater than or equal to twofold in Tex15 germ cells Miwi2 / and Mov10l1 / mutants, in which TEs are de- (Fig. 1D; Supplemental Table S2). At E18.5, a large number repressed (Carmell et al. 2007; Zheng et al. 2010). To as- of transposon families in three classes of retrotransposons sess the potential for TE derepression, we focused on the (LINE1, ERVK, and ERV1) exhibited more pronounced up- expression of LINE1 (non-LTR retrotransposons) and IAP − − regulation in Tex15 / germ cells. Compared with E18.5, (LTR retrotransposons). LINE1 is the most abundant ret- − − the up-regulation level of most TEs in Tex15 / germ cells rotransposon and, while most retrotransposons have de- at P2.5 was reduced, although some (L1Md_A, IAPEz-int, generated due to mutations, ∼100 copies of LINE1 in the IAPLTR2a, IAPLTR2b, and RLTR1B-int) remained com- human genome and ∼3000 copies in the mouse genome parable, and two (IAPLTR1_Mm and MER67D) were remain competent for retrotransposition (Mandal and more highly expressed. The different patterns of TE desi- Kazazian 2008). To assess LINE1 expression, we moni- lencing might be attributed to the dynamic nature of tored the expression of LINE1orf1, an abundantly ex- epigenetic reprogramming in male germ cells during pressed LINE1-encoded structural protein. As expected, − this period and the diverse silencing mechanisms of dif- LINE1 expression was not detected in E17.5 Tex15+/ con- ferent TE families (Yang and Wang 2016).
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