Mettl3-/Mettl14-mediated mRNA N 6-methyladenosine modulates murine spermatogenesis

Zhen Lin; Phillip J. Hsu; Xudong Xing; Jianhuo Fang; Zhike Lu; Qin Zou; Ke Jia Zhang; Xiao Zhang; Yuchuan Zhou; Teng Zhang; Youcheng Zhang; Wanlu Song; Guifang Jia; Xuerui Yang; Chuan He; Ming Han Tong

doi:10.1038/cr.2017.117

Mettl3-/Mettl14-mediated mRNA N 6-methyladenosine modulates murine spermatogenesis

Zhen Lin, Phillip J. Hsu, Xudong Xing, Jianhuo Fang, Zhike Lu, Qin Zou, Ke Jia Zhang, Xiao Zhang, Yuchuan Zhou, Teng Zhang, Youcheng Zhang, Wanlu Song, Guifang Jia, Xuerui Yang, Chuan He, Ming Han Tong^*

^*Corresponding author for this work

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

319 Citations (Scopus)

Abstract

Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N 6-methyladenosine (m 6 A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m 6 A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A 1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m 6 A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m 6 A and depletion of SSCs. m 6 A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m 6 A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

Original language	English
Pages (from-to)	1216-1230
Number of pages	15
Journal	Cell Research
Volume	27
Issue number	10
DOIs	https://doi.org/10.1038/cr.2017.117
Publication status	Published - 1 Oct 2017
Externally published	Yes

Keywords

Mettl14
Mettl3
mA RNA modifcation
spermatogonial stem cell
spermiogenesis

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10.1038/cr.2017.117

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title = "Mettl3-/Mettl14-mediated mRNA N 6-methyladenosine modulates murine spermatogenesis",

abstract = "Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N 6-methyladenosine (m 6 A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m 6 A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A 1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m 6 A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m 6 A and depletion of SSCs. m 6 A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m 6 A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.",

keywords = "Mettl14, Mettl3, mA RNA modifcation, spermatogonial stem cell, spermiogenesis",

author = "Zhen Lin and Hsu, {Phillip J.} and Xudong Xing and Jianhuo Fang and Zhike Lu and Qin Zou and Zhang, {Ke Jia} and Xiao Zhang and Yuchuan Zhou and Teng Zhang and Youcheng Zhang and Wanlu Song and Guifang Jia and Xuerui Yang and Chuan He and Tong, {Ming Han}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

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doi = "10.1038/cr.2017.117",

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T1 - Mettl3-/Mettl14-mediated mRNA N 6-methyladenosine modulates murine spermatogenesis

AU - Lin, Zhen

AU - Hsu, Phillip J.

AU - Xing, Xudong

AU - Fang, Jianhuo

AU - Lu, Zhike

AU - Zou, Qin

AU - Zhang, Ke Jia

AU - Zhang, Xiao

AU - Zhou, Yuchuan

AU - Zhang, Teng

AU - Zhang, Youcheng

AU - Song, Wanlu

AU - Jia, Guifang

AU - Yang, Xuerui

AU - He, Chuan

AU - Tong, Ming Han

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N 6-methyladenosine (m 6 A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m 6 A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A 1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m 6 A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m 6 A and depletion of SSCs. m 6 A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m 6 A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

AB - Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N 6-methyladenosine (m 6 A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m 6 A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A 1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m 6 A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m 6 A and depletion of SSCs. m 6 A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m 6 A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

KW - Mettl14

KW - Mettl3

KW - mA RNA modifcation

KW - spermatogonial stem cell

KW - spermiogenesis

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U2 - 10.1038/cr.2017.117

DO - 10.1038/cr.2017.117

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SN - 1001-0602

VL - 27

SP - 1216

EP - 1230

JO - Cell Research

JF - Cell Research

IS - 10

ER -

Mettl3-/Mettl14-mediated mRNA N 6-methyladenosine modulates murine spermatogenesis

Abstract

Keywords

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