No abstract

Traditionally, we know that genomic DNA will produce transcripts named messenger RNA and then translate into protein following the instruction of genetic central dogma, and RNA works here as a pass-by messenger. Now increasing evidence shows that RNA is a key regulator as well as a message transmitter. It is discovered by next-generation sequencing techniques that most genomic DNA are generally transcribed to non-coding RNA, highly beyond the percentage of coding mRNA. These non-coding RNAs (ncRNAs), belonging to several groups, have critical roles in many cellular processes, expanding our understanding of the RNA world. We review here the different categories of ncRNA according to genome location and how ncRNAs guide and recruit chromatin modification complex to specific loci of genome to modulate gene expression by affecting chromatin state.

The well-established functions of UHRF1 converge to DNA biological processes, as exemplified by DNA methylation maintenance and DNA damage repair during cell cycles. However, the potential effect of UHRF1 on RNA metabolism is largely unexplored. Here, we revealed that UHRF1 serves as a novel alternative RNA splicing regulator. The protein interactome of UHRF1 identified various splicing factors. Among them, SF3B3 could interact with UHRF1 directly and participate in UHRF1-regulated alternative splicing events. Furthermore, we interrogated the RNA interactome of UHRF1, and surprisingly, we identified U snRNAs, the canonical spliceosome component, in the UHRF1-associated RNA components. Unexpectedly, we found H3R2 methylation status determines the binding preference of U snRNA, especially U2 snRNA. The involvement of U snRNAs in UHRF1-containing complex and their binding preference to specific chromatin configuration imply a finely orchestrated mechanism at play. Our results provided the resources and pinpointed the molecular basis of UHRF1-mediated alternative RNA splicing, which will help us better our understanding of the physiological and pathological roles of UHRF1 in disease development.

Background A whole-exome or targeted cancer genes panel by next-generation sequencing has been used widely in assisting individualized treatment decisions. Currently, multiple algorithms are developed to estimate DNA copy numbers based on sequencing data, which makes a comprehensive global glance at chromosomal integrity possible. We aim to classify gastric cancers based on chromosomal integrity to guide personalized therapy. Methods We investigated copy number variations (CNV) across the entire genome of 124 gastric carcinomas via exome or targeted sequencing. Chromosomal integrity was classified as chromosomal stability (CS), chromosomal instability (CIN) and intermediate state (CIN/CS) based on CNV results. Chromosomal integrity was correlated to molecular features and clinical characteristics. Results According the states of chromosomal integrity, gastric carcinomas can be stratified into two cohorts: CS and CIN. Our results showed a significant relationship between CIN status and TP53 mutation, but not RB1, phosphatase and tensin homolog (PTEN), or other reported DNA damage repair genes. The mutation frequency of the TP53 gene had great relevance. Our study initially revealed clinical significance of chromosomal integrity that CIN patients were prone to HER2-positive and mucinous adenocarcinoma, while CS patients were a diffuse subtype and poorly differentiated but had longer overall survival. Conclusions We classified gastric carcinomas into two states of chromosomal integrity with clinical implications. The dichotomy is applicable to clinical transformation. We proposed that classifying gastric cancers based on chromosomal integrity would enable us to achieve personalized therapy for patients and may be beneficial to patient stratification in future clinical trials.