Biology subjects

Toma, M. A.

Publications and source records attributed to Toma, M. A..

3 recordsLinked to original sources

bioRxiv2024

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing

Both circular RNAs (circRNA) and microRNAs (miRNA) have emerged to play important roles in health and disease. To understand their function in tissue repair, we profiled circRNA, linear RNA, and miRNA expression dynamics in human wound-edge keratinocytes across the wound healing process. Our investigation spotlighted circASH1L(4,5) and its engagement with miR-129-5p, both of which levels were increased with wound repair. Unlike conventional miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting this miRNA from target-directed miRNA degradation (TDMD) triggered by NR6A1 mRNA. TGF-{beta} signaling, pivotal in wound healing, fostered circASH1L expression while suppressing NR6A1, thus enhancing the miR-129 abundance at the post-transcriptional level. Functionally, circASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Collectively, our study uncovers circRNAs novel role as shields for miRNAs and sheds light on the physiological importance of regulated miRNA degradation in human skin wound healing.

molecular biology↗

bioRxiv2021

Genome-wide, integrative analysis of microRNA-mediated gene regulation in human wounds reveals cooperating microRNAs as therapeutic targets

MicroRNAs (miR) are important posttranscriptional regulators and exhibit a high potential to be utilized in diagnosis and therapy. However, our insufficient knowledge of the miR-mediated gene regulation in human skin wound healing severely hinders the identification of clinically relevant miRs. Here, we performed paired small RNA and long RNA sequencing in human tissue samples, including matched skin and acute wounds collected at each healing stage and chronic non-healing venous ulcers (VU). With integrative small and long RNA-omics analysis, we developed a compendium (https://www.xulandenlab.com/humanwounds-mirna-mrna), which will be an open, comprehensive resource to broadly aid wound healing research. With this first clinical, wound-centric resource of miRs and mRNAs, we identified 17 pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. Intermeshing regulatory networks controlled by these miRs revealed their high cooperativity in contributing to chronic wound pathology characterized by persistent inflammation and proliferative phase initiation failure. Furthermore, we demonstrated that miR-34a, miR-424, and miR-516, upregulated in VU, cooperatively suppressed keratinocyte growth while promoting inflammatory response. Collectively, our study opens the possibility of developing innovative wound treatment that targets pathologically relevant cooperating miRs to attain higher therapeutic efficacy and specificity.

systems biology↗

bioRxiv2021

Circular RNA signatures of human healing and non-healing wounds

BackgroundAlthough the widespread expression of circular RNAs (circRNAs) has only been recognized recently, increasing evidence has suggested their important roles in health and disease. To identify clinically relevant circRNAs with potential for wound diagnosis and therapy, an in-depth characterization of circRNA expression in human healing and non-healing wounds is a prerequisite that has not been attained yet. MethodsWe collected wound-edge biopsies through the healing process of healthy donors and in chronic non-healing venous ulcers (VU). Paired total RNA- and small RNA-sequencing were performed to profile circRNAs, protein-coding mRNAs, and microRNA expression. We analyzed the co-expression relationship between circRNAs and mRNAs with weighted correlation network analysis (WGCNA) and constructed circRNA-microRNA-mRNA networks. For the circRNAs surfaced in the in-silico analysis, after validating their expression with RT-PCR and sequencing, we silenced hsa-CHST15_0003 and hsa-TNFRSF21_0001 expression in keratinocytes with siRNAs and studied their function with transcriptomic profiling and live-cell monitoring. ResultsOur study unravels the dynamically changed expression patterns of circRNAs during human skin wound healing and their abnormal expression signature in VU, which are presented as a searchable web resource (http://130.229.28.87/shiny/circRNA_wholebiopsy-shinyApp/). In silico analysis deciphers the circRNA-miRNAs-mRNA networks specific to the inflammatory and proliferative phases of wound repair and VU, the biological processes that circRNAs are involved, and the circRNAs that could act as miRNAs sponge in human wounds. Importantly, we found that hsa-CHST15_0003 and hsa-TNFRSF21_0001, two circRNAs upregulated in VU, hampered keratinocyte migration while promoting proliferation through modulating gene networks underpinning these cellular processes. ConclusionBy integrating circRNA, mRNA, and miRNA expression profiles in a unique collection of clinical samples, we identify the circRNAs that are relevant to human wound healing physiology and pathology. This study paves the way to decipher the functional significance of circRNAs in tissue repair.

cell biology↗