Conserved microRNAs and Flipons Shape Gene Expression during Development by Altering Promoter Conformations

Area of Science:

• Molecular Biology
• Genetics
• Epigenetics

Background:

• Classical gene regulation models focus on prokaryotic operons and protein-DNA interactions.
• Eukaryotic gene regulation involves microRNAs (miRs) modulating transcript readout and flipons influencing DNA-based genetic programs.
• The interplay between miR and flipon mechanisms in eukaryotes remains largely unexplored.

Purpose of the Study:

• To investigate the connection between flipon conformation and conserved human microRNAs (c-miRs).
• To identify specific c-miRs that interact with flipons and their functional implications.
• To propose a model for combinatorial miR action in regulating genetic information readout via flipon formation.

Main Methods:

• Sequence alignment analysis to identify potential interactions between c-miRs and flipons.
• Experimental validation of flipon engagement with argonaute proteins.
• Bioinformatic analysis of flipon enrichment in gene promoters associated with specific biological functions.
• Identification of c-miRs targeting flipons involved in retrotransposon replication.

Main Results:

• Direct interaction between c-miRs and flipons is supported by sequence data and argonaute protein engagement.
• Flipons are significantly enriched in promoters of genes crucial for multicellular development, cell surface glycosylation, and glutamatergic synapse specification.
• A subset of c-miRs targets flipons essential for limiting retrotransposon replication.
• Specific examples include hsa-miR-324-3p interacting with RELA and hsa-miR-744 with ARHGAP5.

Conclusions:

• MicroRNAs and flipons represent a deeply interconnected regulatory system in eukaryotes.
• Conserved miRs play a critical role in specifying flipon formation, thereby controlling gene expression and genome stability.
• This combinatorial miR-flipon mechanism regulates the readout of genetic information at the DNA level, influencing key biological processes and defense against mobile genetic elements.