C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

Ansgar Zoch; Gabriela Konieczny; Tania Auchynnikava; Birgit Stallmeyer; Nadja Rotte; Madeleine Heep; Rebecca V. Berrens; Martina Schito; Yuka Kabayama; Theresa Schöpp; Sabine Kliesch; Brendan Houston; Liina Nagirnaja; Moira K. O’Bryan; Kenneth I. Aston; Donald F. Conrad; Juri Rappsilber; Robin C. Allshire; Atlanta G. Cook; Frank Tüttelmann; Dónal O’Carroll

doi:10.1016/j.molcel.2024.01.014

C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

Ansgar Zoch, Gabriela Konieczny, Tania Auchynnikava, Birgit Stallmeyer, Nadja Rotte, Madeleine Heep, Rebecca V. Berrens, Martina Schito, Yuka Kabayama, Theresa Schöpp, Sabine Kliesch, Brendan Houston, Liina Nagirnaja, Moira K. O’Bryan, Kenneth I. Aston, Donald F. Conrad, Juri Rappsilber, Robin C. Allshire, Atlanta G. Cook, Frank TüttelmannDónal O’Carroll

Research output: Contribution to journal › Article › peer-review

Abstract

Summary In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.

Original language	English
Pages (from-to)	1021
Number of pages	27
Journal	Molecular Cell
Volume	84
Issue number	6
Early online date	14 Feb 2024
DOIs	https://doi.org/10.1016/j.molcel.2024.01.014
Publication status	Published - 21 Mar 2024

Keywords / Materials (for Non-textual outputs)

germline
transposon
DNA methylation
piRNA
PIWI
DNMT3C
human male fertility

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10.1016/j.molcel.2024.01.014

1-s2.0-S1097276524000509-mainFinal published version, 5.9 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.sciencedirect.com/science/article/pii/S1097276524000509

Core funding for the Wellcome Centre for Cell Biology
Marston, A. (Principal Investigator)
UK-based charities
1/12/21 → 30/11/23
Project: Research
Epigenetic inheritance: establishment and transmission of specialised chromatin domains
Allshire, R. (Principal Investigator)
UK-based charities
1/04/17 → 31/03/23
Project: Research
Wellcome Centre for Cell Biology
Tollervey, D. (Principal Investigator)
UK-based charities
1/12/16 → 1/12/21
Project: Research

Cite this

Zoch, A., Konieczny, G., Auchynnikava, T., Stallmeyer, B., Rotte, N., Heep, M., Berrens, R. V., Schito, M., Kabayama, Y., Schöpp, T., Kliesch, S., Houston, B., Nagirnaja, L., O’Bryan, M. K., Aston, K. I., Conrad, D. F., Rappsilber, J., Allshire, R. C., Cook, A. G., ... O’Carroll, D. (2024). C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line. Molecular Cell, 84(6), 1021. https://doi.org/10.1016/j.molcel.2024.01.014

@article{bb90e394cc72494290406576e3baa1a8,

title = "C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line",

abstract = "Summary In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.",

keywords = "germline, transposon, DNA methylation, piRNA, PIWI, DNMT3C, human male fertility",

author = "Ansgar Zoch and Gabriela Konieczny and Tania Auchynnikava and Birgit Stallmeyer and Nadja Rotte and Madeleine Heep and Berrens, \{Rebecca V.\} and Martina Schito and Yuka Kabayama and Theresa Sch{\"o}pp and Sabine Kliesch and Brendan Houston and Liina Nagirnaja and O{\textquoteright}Bryan, \{Moira K.\} and Aston, \{Kenneth I.\} and Conrad, \{Donald F.\} and Juri Rappsilber and Allshire, \{Robin C.\} and Cook, \{Atlanta G.\} and Frank T{\"u}ttelmann and D{\'o}nal O{\textquoteright}Carroll",

note = "We acknowledge the EMBL GeneCore facility in Heidelberg, Germany, for preparing the EM-seq dataset of P14 spermatogonia and sequencing all next-generation sequencing libraries. The authors thank David Kelly at the Wellcome Centre for Cell Biology Centre for Optical Instrumentation Laboratory (COIL) and Matthieu Vermeren at the Centre for Regenerative Medicine Imaging Core Facility for microscopy and instrumentation support; Christos Spanos at the Wellcome Centre for Cell Biology Proteomics Facility for support with mass spectrometry analysis; the Shared University Research Facilities (SURF) histology and histological imaging facility for support with histology of mouse samples; Fiona Rossi at the Centre for Regenerative Medicine Flow Cytometry Facility for handling cell sorting of spermatogonia; and Theresa O{\textquoteright}Connor at the Centre for Regenerative Medicine Tissue Culture Facility for providing cell culture facilities. ",

year = "2024",

month = mar,

day = "21",

doi = "10.1016/j.molcel.2024.01.014",

language = "English",

volume = "84",

pages = "1021",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "6",

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Zoch, A, Konieczny, G, Auchynnikava, T, Stallmeyer, B, Rotte, N, Heep, M, Berrens, RV, Schito, M, Kabayama, Y, Schöpp, T, Kliesch, S, Houston, B, Nagirnaja, L, O’Bryan, MK, Aston, KI, Conrad, DF, Rappsilber, J, Allshire, RC , Cook, AG, Tüttelmann, F & O’Carroll, D 2024, 'C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line', Molecular Cell, vol. 84, no. 6, pp. 1021. https://doi.org/10.1016/j.molcel.2024.01.014

TY - JOUR

T1 - C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

AU - Zoch, Ansgar

AU - Konieczny, Gabriela

AU - Auchynnikava, Tania

AU - Stallmeyer, Birgit

AU - Rotte, Nadja

AU - Heep, Madeleine

AU - Berrens, Rebecca V.

AU - Schito, Martina

AU - Kabayama, Yuka

AU - Schöpp, Theresa

AU - Kliesch, Sabine

AU - Houston, Brendan

AU - Nagirnaja, Liina

AU - O’Bryan, Moira K.

AU - Aston, Kenneth I.

AU - Conrad, Donald F.

AU - Rappsilber, Juri

AU - Allshire, Robin C.

AU - Cook, Atlanta G.

AU - Tüttelmann, Frank

AU - O’Carroll, Dónal

N1 - We acknowledge the EMBL GeneCore facility in Heidelberg, Germany, for preparing the EM-seq dataset of P14 spermatogonia and sequencing all next-generation sequencing libraries. The authors thank David Kelly at the Wellcome Centre for Cell Biology Centre for Optical Instrumentation Laboratory (COIL) and Matthieu Vermeren at the Centre for Regenerative Medicine Imaging Core Facility for microscopy and instrumentation support; Christos Spanos at the Wellcome Centre for Cell Biology Proteomics Facility for support with mass spectrometry analysis; the Shared University Research Facilities (SURF) histology and histological imaging facility for support with histology of mouse samples; Fiona Rossi at the Centre for Regenerative Medicine Flow Cytometry Facility for handling cell sorting of spermatogonia; and Theresa O’Connor at the Centre for Regenerative Medicine Tissue Culture Facility for providing cell culture facilities.

PY - 2024/3/21

Y1 - 2024/3/21

N2 - Summary In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.

AB - Summary In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.

KW - germline

KW - transposon

KW - DNA methylation

KW - piRNA

KW - PIWI

KW - DNMT3C

KW - human male fertility

U2 - 10.1016/j.molcel.2024.01.014

DO - 10.1016/j.molcel.2024.01.014

M3 - Article

SN - 1097-2765

VL - 84

SP - 1021

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Core funding for the Wellcome Centre for Cell Biology

Epigenetic inheritance: establishment and transmission of specialised chromatin domains

Wellcome Centre for Cell Biology

Cite this