IGF2BP3 recognizes m⁶A to regulate histone-to-protamine replacement during mouse sperm development

Area of Science:

• Reproductive Biology
• Molecular Biology
• Epigenetics

Background:

• Spermatid development relies on RNA metabolism, including N6-methyladenosine (m6A) modifications.
• The roles of specific m6A reader proteins in post-meiotic spermiogenesis are not well understood.

Purpose of the Study:

• To investigate the function of the m6A reader protein IGF2BP3 in post-meiotic spermatid development.
• To elucidate the regulatory mechanisms by which IGF2BP3 controls sperm development.

Main Methods:

• Utilized genetic ablation (knockout) of Igf2bp3 in mice.
• Investigated RNA translation and protein interactions.
• Employed siRNA to target specific genes (Dot1l, Hdac11) for rescue experiments.

Main Results:

• Igf2bp3 deficiency caused spermatogenesis defects and male sub-fertility/infertility.
• Loss of IGF2BP3 led to increased translation of target RNAs (Dot1l, Hdac11) involved in histone-to-protamine replacement.
• IGF2BP3 translationally represses targets via m6A binding and YBX2 interaction.
• Knockout phenotypes were rescued by targeting Dot1l and Hdac11.

Conclusions:

• IGF2BP3 is essential for regulating protein biosynthesis during spermiogenesis, specifically in histone-to-protamine replacement.
• This study clarifies the role of m6A RNA modification in male fertility and sperm development.