Khorasani, S. | bioRxiv Science

bioRxiv2021

Somatic point mutations are enriched in long non-coding RNAs with possible regulatory function in breast cancer

De novo somatic point mutations identified in breast cancer are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, while the non-coding RNAs (ncRNAs) form a large portion of the mammalian genome, their biological functions are mostly poorly characterized in cancers. In this study, using a newly developed tool, SomaGene, we reanalyze de novo somatic point mutations from the International Cancer Genome Consortium (ICGC) whole-genome sequencing data of 1,855 breast cancers. We identify 929 candidates of ncRNAs that are significantly and explicitly mutated in breast cancer samples. By integrating data from the ENCODE regulatory features and FANTOM5 expression atlas, we show that the candidate ncRNAs in breast cancer samples significantly enrich for active chromatin histone marks (1.9 times), CTCF binding sites (2.45 times), DNase accessibility (1.76 times), HMM predicted enhancers (2.26 times) and eQTL polymorphisms (1.77 times). Importantly, we show that the 929 ncRNAs contain a much higher level (3.64 times) of breast cancer-associated genome-wide association (GWAS) single nucleotide polymorphisms (SNPs) than genome-wide expectation. Such enrichment has not been seen with GWAS SNPs from other diseases. Using breast tissue related Hi-C data we then show that 82% of our candidate ncRNAs (1.9 times) significantly interact with the promoter of protein-coding genes, including previously known cancer-associated genes, suggesting the critical role for candidate ncRNA genes in activation of essential regulators of development and differentiation in breast cancer. We provide an extensive web-based resource (http://ncrna.ictic.sharif.edu), to communicate our results with the research community. Our list of breast cancer-specific ncRNA genes has the potential to provide a better understanding of the underlying genetic causes of breast cancer. Lastly, the tool developed in this study can be used in the analysis of somatic mutations in all cancers.

cancer biology↗

bioRxiv2018

A genome-wide screen identifies genes in rhizosphere-associated Pseudomonas required to evade plant defenses

Pseudomonas fluorescens and related plant root- (\"rhizosphere\") associated species contribute to plant health by modulating defenses and facilitating nutrient uptake. To identify bacterial fitness determinants in the rhizosphere of the model plant Arabidopsis thaliana, we performed a Tn-Seq screen using the biocontrol and growth-promoting strain Pseudomonas sp. WCS365. The screen, which was performed in parallel on wild-type and an immunocompromised Arabidopsis, identified 231 genes that positively affect fitness in the rhizosphere of wild-type plants. A subset of these genes negatively affect fitness in the rhizosphere of immunocompromised plants. We postulated that these genes might be involved in avoiding plant defenses and verified 7 Pseudomonas sp. WCS365 candidate genes by generating clean deletions. We found that two of these deletion strains, {Delta}morA (encodes a putative diguanylate cyclase/phosphodiesterase) and {Delta}spuC (encodes a putrescine aminotransferase) formed enhanced biofilms and inhibited plant growth. Inhibition of plant growth by {Delta}spuC and {Delta}morA was the result of pattern triggered immunity (PTI) as measured by induction of an Arabidopsis PTI reporter and FLS2/BAK1-dependent inhibition of plant growth. We found that MorA acts as a phosphodiesterase to inhibit biofilm formation suggesting a possible role in biofilm dispersal. We found that both putrescine and its precursor arginine promote biofilm formation that is enhanced in the {Delta}spuC mutant, which cannot break down putrescine suggesting that putrescine might serve as a signaling molecule in the rhizosphere. Collectively, this work identified novel bacterial factors required to evade plant defenses in the rhizosphere.\n\nImportanceWhile rhizosphere bacteria hold the potential to improve plant health and fitness, little is known about the bacterial genes required to evade host immunity. Using a model system consisting of Arabidopsis and a beneficial Pseudomonas sp. isolate, we identified bacterial genes required for both rhizosphere fitness and for evading host immune responses. This work advances our understanding of how evasion of host defenses contributes to survival in the rhizosphere.

microbiology↗