Insights into the evolution and regulation of miRNAs from the view of their DNA replication temporal domains.

Authors

Xudong Wu, Tingting Liu

Published in

Frontiers in genetics. Volume 16. Pages 1544802. Epub Jun 23, 2025.

Abstract

The DNA replication of eukaryotes proceeds in a defined temporal sequence known as the replication timing (RT) program. A recent study revealed that the early- and late-replication temporal domains have different DNA mutation patterns and that the late-replicating sequences have a substitution pattern biased towards A and T. It raises the interesting question of how the miRNAs in the late-replication domain cope with the mutation bias caused by RT.
In this study, we characterized the genomic distribution of pre-miRNAs in relation to DNA replication timing, and identified 362 pre-miRNAs within late-replicating domains (late-miRNAs) and 631 pre-miRNAs within early-replicating domains (early-miRNAs). We comprehensively examined the multiple molecular features including the secondary structural properties, the genomic sequences surrounding the pre-miRNA loci, the Dicer processing motifs, and CAGE tag-based promoters and miRNAs expression profiles. Furthermore, we performed the simulation of miRNA-target regulatory networks to elucidate the co-regulation patterns among late-miRNAs. To advance predictive capabilities, we developed a a support vector machine (SVM) classifier based on RNA-FM embedding, enabling prediction of miRNAs' replication timing domains.
Our study indicated that the late pre-miRNAs maintained their ability to fold into hairpin structures through extending their lengths at both ends under the premise of maintaining a certain GC content of the precursors. The simulation demonstrated that the late-miRNAs tend to synergistically regulate the same genes and are involved in small molecule metabolism, immune responses and so on. The comparative analysis of early- and late- miRNAs confirmed that the information of replication timing domains is inherently encoded in miRNAs' sequence-structure signatures, and suggested that late-replication specific mutation patterns leave direct imprints on miRNA architecture. This study provides insights into the impact of DNA replication timing on miRNA-mediated posttranscriptional regulation and helps us understand the evolutionary mechanism of miRNAs.

PMID:
40626175
Bibliographic data and abstract were imported from PubMed on 08 Jul 2025.

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