m ⁶ A-dependent microRNA binding to chromatin-associated RNA for transcriptional activation

Area of Science:

• Epigenetics
• RNA Biology
• Gene Regulation

Background:

• MicroRNAs (miRNAs) are traditionally known for post-transcriptional gene silencing.
• The role of miRNAs in transcriptional regulation remains less understood.
• Chromatin-associated RNAs (caRNAs) are emerging as key regulatory elements in gene expression.

Purpose of the Study:

• To investigate the novel function of microRNAs (miRNAs) in gene transcription.
• To uncover the mechanism of miRNA-mediated transcriptional activation.
• To explore the role of m6A modification in small RNA-directed gene regulation.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) to identify protein-RNA interactions.
• RNA sequencing (RNA-seq) to assess gene expression changes.
• Biochemical assays to study protein complex formation and function.

Main Results:

• Extensive binding of miRNAs to chromatin-associated RNAs (caRNAs) was discovered.
• A novel mechanism for miRNA-dependent transcriptional activation mediated by m6A modification was uncovered.
• m6A-binding proteins FXR1/2 anchor AGO1/2 at m6A-marked caRNAs, guiding miRNA action.
• Recruitment of SMARCA4 (BRG1) and TET1 leads to chromatin opening and DNA demethylation.
• This process enhances gene accessibility and transcription across numerous genes.

Conclusions:

• MicroRNAs (miRNAs) possess a previously unrecognized function in activating gene transcription.
• The m6A-modified caRNA pathway provides a new mechanism for epigenetic gene regulation by small RNAs.
• This finding broadens the known roles of small RNAs in gene expression, extending beyond post-transcriptional repression.