Multiple repeat regions within mouse DUX recruit chromatin regulators to facilitate an embryonic gene expression...

Area of Science:

• Developmental Biology
• Epigenetics
• Gene Regulation

Background:

• The embryonic transcription factor DUX is crucial for chromatin opening and gene expression in early mouse embryos.
• DUX expression in embryonic stem cells drives conversion to 2-cell embryo-like cells (2CLCs) with extraembryonic potential.
• Specific domains of mouse DUX and their interactions with chromatin/transcription regulators are largely unknown.

Approach:

• Structure-function analyses identified two 'active' and three 'inactive' C-terminal repeats in DUX, with a key 6 amino acid region differentiating their function.
• Proximity-dependent biotin ligation (BioID) identified proteins associated with active DUX repeat derivatives.
• Mechanistic studies explored the interplay between DUX active repeats, its acidic tail, and cofactor recruitment.

Key Points:

• The C-terminus of mouse DUX comprises five ~100 amino acid repeats and a 14 amino acid acidic tail.
• A critical 6 amino acid sequence within DUX repeats dictates their activity in regulating the cleavage/2CLC transcription program.
• Active DUX repeats and the acidic tail cooperate in recruiting cofactors, opening DUX targets, and driving transcription.
• BioID revealed associations of active DUX repeats with SWI/SNF (BAF) complex, nucleolar factors, and other chromatin regulators.

Conclusions:

• This study elucidates novel structure-function relationships within the mouse DUX protein.
• Identifies specific DUX domains critical for regulating chromatin and gene expression in early embryonic development.
• Provides mechanistic insights into how DUX interacts with chromatin modifiers and transcription factors to control gene programs.