Reciprocal modulation of Linc-223 and its ligand miR-125a on the basis of platelet function level

Background Cardiovacular diseases (CVD) are the leading cause of death worldwide. Platelet play a key role in the pathophysiology of multiple CVD. LincRNAs are long non-coding RNAs transcribed from intergenic DNA segments. Some members of this class were recently associated with human disease. Linc-223 is co-transcribed together with mir-223 and was recently shown to bind to miR-125. Both miR-223 and miR-125 are highly expressed in platelets. Purpose In light of the capability of Linc-223 to bind to miR-125, we aimed to investigate whether their reciprocal expression levels might reflect the degree of platelet activity. Methods RNA was extracted using miRVANA. MiRNAs and lncRNAs were measured by means of quantitative Real Time RT-PCR. Results We found a significant reduction of Linc-223 levels (p<0.05) along with a significant increase in miR-125 levels (p<0.05) after initiation of any antiplatelet treatment (n=30) compared to naïve patients (n=10). Moreover, the upgrade to a higher-intensity antiplatelet treatment with ASA+ticagrelor from ASA+clopidogrel (n=30) was associated to a further down-regulation of Linc-223 (p<0.05) along with a further increase of miR-125. (p<0.05). Finally, these results were validated in a larger cohort of 300 patients from the ATLANTIS study, demonstrating significant modulation of both miR-223 and miR-125 in patients with high on-treatment platelet aggregation levels compared to antiplatelet-responsive patients. Conclusions We identify a reciprocal modulation of Linc-223 and miR-125, its ligand upon different levels of platelet aggregations. These results are compatible with previous evidence from patients with Acute Myeloid Leukemia, that Linc-223 might bind to and sponge miR-125, inhibiting its effect. These results suggest that plasma levels of Linc-223, miR-125 and miR-223 might be used a biomarkers of platelet finction in a clinical context, for risk stratification of patients or to assess the responsiveness to antiplatelet treatments. Funding Acknowledgement Type of funding source: None

Correction to: DNMT3A reads and connects histone H3K36me2 to DNA methylation

The author would like to add the below information in this correction. A similar study from Chao Lu group was published online on 5 September 2019 in Nature, entitled “The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape” (Weinberg et al., 2019). Although both the studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP, ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A. On the disease connections, we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers, while the other study only used NSD1 and DNMT3A loss-of-function models.