m⁶A reader Ythdf proteins control retrotransposon B2 repeat expression and safeguard early embryo development.

Area of Science:

• Molecular Biology
• Developmental Biology
• Epigenetics

Background:

• N⁶-methyladenosine (m⁶A) modification and its reader proteins are vital for mammalian gene expression and development.
• The precise roles of m⁶A reader proteins Ythdf1, Ythdf2, and Ythdf3 in early mammalian embryogenesis are not fully understood.

Purpose of the Study:

• To investigate the function of Ythdf1, Ythdf2, and Ythdf3 proteins in early mouse embryo development.
• To elucidate the molecular mechanisms by which Ythdf proteins regulate gene expression during embryogenesis.

Main Methods:

• Conditional knockout mouse models to study Ythdf protein function in vivo.
• RNA sequencing and transcriptomic analysis to identify target RNAs and gene expression changes.
• Analysis of RNA polymerase II and III activity in Ythdf-deficient embryos.

Main Results:

• Ythdf2 and Ythdf3, but not Ythdf1, are indispensable for early mouse embryo development.
• All three Ythdf proteins facilitate the decay of target transcripts, including maternal mRNAs, activated transcripts, and retrotransposon RNAs.
• Retrotransposon B2 RNAs are key targets; their accumulation in Ythdf1-3 deficient embryos impairs RNA polymerase II transcription via trans-regulation and represses Pol III-driven B2 transcription via cis-regulation.

Conclusions:

• A coordinated regulatory network involving Ythdf proteins and SINE/B2 RNAs is critical for orchestrating gene expression during embryogenesis.
• Ythdf proteins play a crucial role in maintaining transcriptional homeostasis by controlling retrotransposon RNA levels during early development.