METTL16 and YTHDC1 Regulate Spermatogonial Differentiation via m6A.

Area of Science:

• Reproductive Biology
• Epigenetics
• Molecular Biology

Background:

• Spermatogenesis involves complex post-transcriptional regulation, including N6-methyladenosine (m6A) modification.
• While METTL3/METTL14 are known m6A writers, their absence in spermatogenesis did not cause defects, suggesting other factors are involved.
• METTL16 is an understudied m6A methyltransferase with potential roles in spermatogenesis.

Purpose of the Study:

• To investigate the role of the m6A methyltransferase METTL16 in spermatogenesis.
• To explore the function of YTHDC1, a reader of METTL16 target genes, in male germ cell development.
• To elucidate the molecular mechanisms underlying m6A-mediated regulation in spermatogonial differentiation.

Main Methods:

• Generation of Mettl16 conditional knockout mice using vasa-cre and Stra8-cre.
• Generation of Ythdc1 conditional knockout mice using Stra8-cre.
• RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq) analyses.
• Histological examination of testes and assessment of spermatogonia populations.

Main Results:

• Mice lacking Mettl16 in germ cells showed reduced testes size and progressive spermatogonia loss.
• Deletion of Mettl16 or Ythdc1 in spermatogonia blocked their differentiation.
• Both Mettl16 and Ythdc1 deficiencies disrupted gene expression related to chromosome organization and segregation.
• These disruptions ultimately led to male infertility in the knockout mice.

Conclusions:

• METTL16 acts as a critical m6A writer, and YTHDC1 as its reader, essential for spermatogonial differentiation.
• The METTL16-YTHDC1 pathway regulates gene expression crucial for male germ cell development.
• Dysregulation of this pathway results in impaired spermatogenesis and male infertility, underscoring its importance in reproductive health.