Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer.

A certain proportion of genes are regulated by multiple, distinct promoters, revealing a dynamic landscape of the cancer transcriptome. However, the contribution of alternative promoters (APs) in breast cancer (BRCA) remains largely unexplored. Here, we identified 3654 genes with multiple promoters in BRCA patients, and 53 of them could generate distinct AP transcripts that are dysregulated and prognosis-related in BRCA, namely prognosis-related dysregulated AP (prdeAP) transcripts. Interestingly, when we searched for the genomic signatures of these prdeAP genes, we found that the promoter regions of 92% of the prdeAP genes were enriched with abundant DNA methylation signals. Through further bioinformatic analysis and experimental validation, we showed that AP selections of TANK, UNKL, CCL28, and MAP1LC3A were regulated by DNA methylation upon their corresponding promoter regions. Functionally, by overexpressing AP variants of TANK, we found that TANK|55731 could dramatically suppress MDA-MB-231 cell proliferation and migration. Meanwhile, pan-cancer survival analyses suggested that AP variants of TANK provided more accurate prognostic predictive ability than TANK gene in a variety of tumor types, including BRCA. Together, by uncovering the DNA methylation-regulated AP transcripts with tumor prognostic features, our work revealed a novel layer of regulators in BRCA progression and provided potential targets that served as effective biomarkers for anti-BRCA treatment.

Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3.

Recent studies have shown that long noncoding RNAs (lncRNAs) are critical regulators in the central nervous system (CNS). However, their roles in the cerebellum are currently unclear. In this work, we identified the isoform 204 of lncRNA Gm2694 (designated as lncRNA-Promoting Methylation (lncRNA-PM)) is highly expressed in the cerebellum and derived from the antisense strand of the upstream region of Cerebellin-1 (Cbln1), a well-known critical cerebellar synaptic organizer. LncRNA-PM exhibits similar spatiotemporal expression pattern as Cbln1 in the postnatal mouse cerebellum and activates the transcription of Cbln1 through Pax6/Mll1-mediated H3K4me3. In mouse cerebellum, lncRNA-PM, Pax6/Mll1, and H3K4me3 are all associated with the regulatory regions of Cbln1. Knockdown of lncRNA-PM in cerebellum causes deficiencies in Cbln1 expression, cerebellar synaptic integrity, and motor function. Together, our work reveals an lncRNA-mediated transcriptional activation of Cbln1 through Pax6-Mll1-H3K4me3 and provides novel insights of the essential roles of lncRNA in the cerebellum.

Development of a Time Projection Chamber Readout with Hybrid Pixel Sensors for Beam Monitoring.

To monitor the position and profile of therapeutic carbon beams in real-time, in this paper, we proposed a system called HiBeam-T. The HiBeam-T is a time projection chamber (TPC) with forty Topmetal-II- CMOS pixel sensors as its readout. Each Topmetal-II- has 72 × 72 pixels with the size of 83 µm × 83 µm. The detector consists of the charge drift region and the charge collection area. The readout electronics comprise three Readout Control Modules and one Clock Synchronization Module. This Hibeam-T has a sensitive area of 20 × 20 cm and can acquire the center of the incident beams. The test with a continuous 80.55 MeV/u 12C6+ beam shows that the measurement resolution to the beam center could reach 6.45 µm for unsaturated beam projections.

Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile.

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease that is associated with poor prognosis. Recent works have revealed the significant roles of miRNA in ccRCC initiation and progression. Comprehensive characterization of ccRCC based on the prognostic miRNAs would contribute to clinicians' early detection and targeted treatment. Here, we performed unsupervised clustering using TCGA-retrieved prognostic miRNAs expression profiles. Two ccRCC subtypes were identified after assessing principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and consensus heatmaps. We found that the two subtypes are associated with distinct clinical features, overall survivals, and molecular characteristics. C1 cluster enriched patients in relatively early stage and have better prognosis while patients in C2 cluster have poor prognosis with relatively advanced state. Mechanistically, we found the differentially expressed genes (DEGs) between the indicated subgroups dominantly enriched in biological processes related to transmembrane transport activity. In addition, we also revealed a miRNA-centered DEGs regulatory network, which severed as essential regulators in both transmembrane transport activity control and ccRCC progression. Together, our work described the molecular heterogeneity among ccRCC cancers, provided potential targets served as effective biomarkers for ccRCC diagnosis and prognosis, and paved avenues to better understand miRNA-directed regulatory network in ccRCC progression.