m6A-dependent microRNA binding to chromatin-associated RNA for transcriptional activation

Zhong, Y.; Zheng, L.; Li, J.; Liu, C.; Wei, J.; Ye, C.; Dou, X.; Liu, B.; Barbosa, E.; Yang, F.; Pitroda, S.; Chen, M.; Weichselbaum, R.; He, C.

doi:10.64898/2026.02.02.703428

bioRxiv · 10.64898/2026.02.02.703428

m6A-dependent microRNA binding to chromatin-associated RNA for transcriptional activation

Zhong, Y.·Zheng, L.·Li, J.·Liu, C.·Wei, J.·Ye, C.·Dou, X.·Liu, B.·Barbosa, E.·Yang, F.·Pitroda, S.·Chen, M.·Weichselbaum, R.·He, C.

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Abstract

For decades, microRNAs (miRNAs) have been canonically viewed as post-transcriptional repressors. We discovered extensive binding of microRNAs to chromatin-associated RNAs (caRNAs) and uncovered an N6-methyladenosine (m6A)-dependent transcriptional activation mechanism of microRNAs. We show that m6A-binding proteins FXR1/2 anchor AGO1/2 at m6A-marked caRNAs, where AAGUGC-seed microRNAs function as guide RNAs to direct AGO positioning. This dual anchoring stabilizes the AGO-microRNA/FXR-m6A complex at specific loci, which in turn recruits the ATP-dependent chromatin remodeler SMARCA4 (BRG1) to promote local chromatin opening and TET1 for DNA demethylation, respectively. Together, these coordinated activities establish a transcriptionally permissive chromatin environment, enhancing accessibility and transcription across hundreds of genes in diverse cell types. Beyond the AAGUGC-seed family, additional microRNAs and siRNAs also enhance transcription, suggesting that caRNA binding and transcriptional activation may represent a broader property of small RNAs.

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Zhong, Y., Zheng, L., Li, J., Liu, C., Wei, J., Ye, C., Dou, X., Liu, B., Barbosa, E., Yang, F., Pitroda, S., Chen, M., Weichselbaum, R., He, C.. 2026-02-03. m6A-dependent microRNA binding to chromatin-associated RNA for transcriptional activation. https://doi.org/10.64898/2026.02.02.703428

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