Developmental changes in DNA methylation of the male germ cells in foetal and prepuberal mice

ABSTRACT Heterochromatin-related epigenetic mechanisms, such as DNA methylation, facilitate pairing of homologous chromosomes during the meiotic prophase of mammalian spermatogenesis. In pro-spermatogonia, de novo DNA methylation plays a key role in completing meiotic prophase and initiating meiotic division. However, the role of maintenance DNA methylation in the regulation of meiosis, especially in the adult, is not well understood. Here, we reveal that NP95 (also known as UHRF1) and DNMT1 – two essential proteins for maintenance DNA methylation – are co-expressed in spermatogonia and are necessary for meiosis in male germ cells. We find that Np95- or Dnmt1-deficient spermatocytes exhibit spermatogenic defects characterized by synaptic failure during meiotic prophase. In addition, assembly of pericentric heterochromatin clusters in early meiotic prophase, a phenomenon that is required for subsequent pairing of homologous chromosomes, is disrupted in both mutants. Based on these observations, we propose that DNA methylation, established in pre-meiotic spermatogonia, regulates synapsis of homologous chromosomes and, in turn, quality control of male germ cells. Maintenance DNA methylation, therefore, plays a role in ensuring faithful transmission of both genetic and epigenetic information to offspring.

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MORC3, a novel MIWI2 association partner, as an epigenetic regulator of piRNA dependent transposon silencing in male germ cells

Scientific Reports ◽

10.1038/s41598-021-98940-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kanako Kojima-Kita ◽

Satomi Kuramochi-Miyagawa ◽

Manabu Nakayama ◽

Haruhiko Miyata ◽

Steven E. Jacobsen ◽

...

Keyword(s):

Dna Methylation ◽

Germ Cells ◽

De Novo ◽

Effector Proteins ◽

P Element ◽

Male Germ Cells ◽

Transposon Silencing ◽

Association Partner ◽

Pirna Pathway

AbstractThe PIWI (P-element-induced wimpy testis)-interacting-RNA (piRNA) pathway plays a crucial role in the repression of TE (transposable element) expression via de novo DNA methylation in mouse embryonic male germ cells. Various proteins, including MIWI2 are involved in the process. TE silencing is ensured by piRNA-guided MIWI2 that recruits some effector proteins of the DNA methylation machinery to TE regions. However, the molecular mechanism underlying the methylation is complex and has not been fully elucidated. Here, we identified MORC3 as a novel associating partner of MIWI2 and also a nuclear effector of retrotransposon silencing via piRNA-dependent de novo DNA methylation in embryonic testis. Moreover, we show that MORC3 is important for transcription of piRNA precursors and subsequently affects piRNA production. Thus, we provide the first mechanistic insights into the role of this effector protein in the first stage of piRNA biogenesis in embryonic TE silencing mechanism.

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Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells

Developmental Biology ◽

10.1016/j.ydbio.2007.05.002 ◽

2007 ◽

Vol 307 (2) ◽

pp. 368-379 ◽

Cited By ~ 145

Author(s):

C.C. Oakes ◽

S. La Salle ◽

D.J. Smiraglia ◽

B. Robaire ◽

J.M. Trasler

Keyword(s):

Dna Methylation ◽

Germ Cells ◽

Male Germ Cells ◽

Genome Wide

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Comprehensive DNA Methylation Analysis of Retrotransposons in Male Germ Cells

Cell Reports ◽

10.1016/j.celrep.2015.07.060 ◽

2015 ◽

Vol 12 (10) ◽

pp. 1541-1547 ◽

Cited By ~ 15

Author(s):

Ippei Nagamori ◽

Hisato Kobayashi ◽

Yusuke Shiromoto ◽

Toru Nishimura ◽

Satomi Kuramochi-Miyagawa ◽

...

Keyword(s):

Dna Methylation ◽

Germ Cells ◽

Methylation Analysis ◽

Male Germ Cells ◽

Dna Methylation Analysis

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Induction of DNA Methylation by Artificial piRNA Production in Male Germ Cells

Current Biology ◽

10.1016/j.cub.2015.01.060 ◽

2015 ◽

Vol 25 (7) ◽

pp. 901-906 ◽

Cited By ~ 21

Author(s):

Daisuke Itou ◽

Yusuke Shiromoto ◽

Yukiho Shin-ya ◽

Chika Ishii ◽

Toru Nishimura ◽

...

Keyword(s):

Dna Methylation ◽

Germ Cells ◽

Male Germ Cells

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MIWI2 as an Effector of DNA Methylation and Gene Silencing in Embryonic Male Germ Cells

Cell Reports ◽

10.1016/j.celrep.2016.08.027 ◽

2016 ◽

Vol 16 (11) ◽

pp. 2819-2828 ◽

Cited By ~ 20

Author(s):

Kanako Kojima-Kita ◽

Satomi Kuramochi-Miyagawa ◽

Ippei Nagamori ◽

Narumi Ogonuki ◽

Atsuo Ogura ◽

...

Keyword(s):

Dna Methylation ◽

Gene Silencing ◽

Germ Cells ◽

Male Germ Cells

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UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells

Nature Communications ◽

10.1038/s41467-019-12455-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Juan Dong ◽

Xiaoli Wang ◽

Congcong Cao ◽

Yujiao Wen ◽

Akihiko Sakashita ◽

...

Keyword(s):

Dna Methylation ◽

Dna Damage ◽

Histone Modification ◽

Dna Damage Response ◽

Germ Cells ◽

Dna Hypomethylation ◽

Male Germ Cells ◽

Arginine Methyltransferase ◽

Male Germline ◽

Damage Response

Abstract DNA methylation, repressive histone marks, and PIWI-interacting RNA (piRNA) are essential for the control of retrotransposon silencing in the mammalian germline. However, it remains unknown how these repressive epigenetic pathways crosstalk to ensure retrotransposon silencing in the male germline. Here, we show that UHRF1 is responsible for retrotransposon silencing and cooperates with repressive epigenetic pathways in male germ cells. Conditional loss of UHRF1 in postnatal germ cells causes DNA hypomethylation, upregulation of retrotransposons, the activation of a DNA damage response, and switches in the global chromatin status, leading to complete male sterility. Furthermore, we show that UHRF1 interacts with PRMT5, an arginine methyltransferase, to regulate the repressive histone arginine modifications (H4R3me2s and H3R2me2s), and cooperates with the PIWI pathway during spermatogenesis. Collectively, UHRF1 regulates retrotransposon silencing in male germ cells and provides a molecular link between DNA methylation, histone modification, and the PIWI pathway in the germline.

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Transcriptional states of retroelement-inserted regions and KRAB zinc finger protein association regulate DNA methylation of retroelements in human male germ cells

10.1101/2021.05.19.444783 ◽

2021 ◽

Author(s):

Kei Fukuda ◽

Yoshinori Makino ◽

Satoru Kaneko ◽

Yuki Okada ◽

Kenji Ichiyanagi ◽

...

Keyword(s):

Dna Methylation ◽

Zinc Finger ◽

Germ Cells ◽

Molecular Mechanisms ◽

Zinc Finger Protein ◽

De Novo ◽

Primordial Germ Cells ◽

Male Germ Cells ◽

Human Male ◽

Human Spermatogenesis

DNA methylation, repressive histone modifications, and PIWI-interacting RNAs are essential for controlling retroelement silencing in mammalian germ lines. Dysregulation of retroelement silencing is associated with male sterility. Although retroelement silencing mechanisms have been extensively studied in mouse germ cells, little progress has been made in humans. Here, we show that the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are associated with DNA methylation of retroelements in human primordial germ cells (hPGCs), and hominoid-specific retroelement SINE-VNTR-Alus (SVA) is subjected to transcription-directed de novo DNA methylation during human spermatogenesis. Furthermore, we show that the degree of de novo DNA methylation in SVAs varies among human individuals, which confers a significant inter-individual epigenetic variation in sperm. Collectively, our results provide potential molecular mechanisms for the regulation of retroelements in human male germ cells.

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