The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence

Ivayla Ivanova; Christian Much; Monica Di Giacomo; Chiara Azzi; Marcos Morgan; Pedro N. Moreira; Jack Monahan; Claudia Carrieri; Anton J. Enright; Dónal O'Carroll

doi:10.1016/j.molcel.2017.08.003

The RNA m⁶A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence

Ivayla Ivanova, Christian Much, Monica Di Giacomo, Chiara Azzi, Marcos Morgan, Pedro N. Moreira, Jack Monahan, Claudia Carrieri, Anton J. Enright (Lead / Corresponding author), Dónal O'Carroll (Lead / Corresponding author)

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Abstract

YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.

Original language	English
Pages (from-to)	1059-1067.e4
Number of pages	13
Journal	Molecular Cell
Volume	67
Issue number	6
Early online date	31 Aug 2017
DOIs	https://doi.org/10.1016/j.molcel.2017.08.003
Publication status	Published - 21 Sept 2017

Keywords

Animals
Binding sites
Female
Fertility
Gene expression regulation, Developmental
Genotype
Infertility, Female
Meiosis
Mice, Inbred C57BL
Mice, Knockout
Oocytes
Phenotype
Protein binding
RNA processing, Post-Transcriptional
RNA, Messenger
RNA-binding proteins
Transcription, Genetic
Transcriptome
Zygote
Journal article

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Cite this

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title = "The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence",

abstract = "YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.",

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author = "Ivayla Ivanova and Christian Much and {Di Giacomo}, Monica and Chiara Azzi and Marcos Morgan and Moreira, {Pedro N.} and Jack Monahan and Claudia Carrieri and Enright, {Anton J.} and D{\'o}nal O'Carroll",

note = "The research leading to these results has received funding from the Wellcome Trust (award 106144). This study was technically supported by EMBL Genomic Core facility as well as by EMBL Monterotondo{\textquoteright}s genome engineering and microscopy core facilities.",

year = "2017",

month = sep,

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doi = "10.1016/j.molcel.2017.08.003",

language = "English",

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journal = "Molecular Cell",

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T1 - The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence

AU - Ivanova, Ivayla

AU - Much, Christian

AU - Di Giacomo, Monica

AU - Azzi, Chiara

AU - Morgan, Marcos

AU - Moreira, Pedro N.

AU - Monahan, Jack

AU - Carrieri, Claudia

AU - Enright, Anton J.

AU - O'Carroll, Dónal

N1 - The research leading to these results has received funding from the Wellcome Trust (award 106144). This study was technically supported by EMBL Genomic Core facility as well as by EMBL Monterotondo’s genome engineering and microscopy core facilities.

PY - 2017/9/21

Y1 - 2017/9/21

N2 - YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.

AB - YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.

KW - Animals

KW - Binding sites

KW - Female

KW - Fertility

KW - Gene expression regulation, Developmental

KW - Genotype

KW - Infertility, Female

KW - Meiosis

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Oocytes

KW - Phenotype

KW - Protein binding

KW - RNA processing, Post-Transcriptional

KW - RNA, Messenger

KW - RNA-binding proteins

KW - Transcription, Genetic

KW - Transcriptome

KW - Zygote

KW - Journal article

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DO - 10.1016/j.molcel.2017.08.003

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SN - 1097-2765

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JO - Molecular Cell

JF - Molecular Cell

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