Biology subjects

Iliopoulou, E.

Publications and source records attributed to Iliopoulou, E..

2 recordsLinked to original sources

bioRxiv2023

Extensive Loss and Gain of Conserved Non-Coding Elements during Early Teleost Evolution

Conserved Non-coding Elements (CNE) in vertebrates are enriched around transcription factor loci associated with development. However, loss and rapid divergence of CNEs has been reported in teleost fish, albeit taking only few genomes into consideration. Taking advantage of the recent increase in high-quality teleost genomes, we focus on studying the evolution of teleost CNEs, carrying out targeted genomic alignments and comparisons within the teleost phylogeny to detect CNEs and reconstruct the ancestral teleost CNE repertoire. This teleost-centric approach confirms previous observations of extensive vertebrate CNE loss early in teleost evolution, but also reveals massive CNE gain in the teleost stem-group over 300 million years ago. Using synteny-based association to link CNEs to their putatively regulated target genes, we show the most teleost gained CNEs are found in the vicinity of orthologous loci involved in transcriptional regulation and embryonic development that are also associated with CNEs in other vertebrates. Moreover, teleost and vertebrate CNEs share a highly similar motif and transcription factor binding site vocabulary. We suggest that early teleost CNE gains reflect a restructuring of the ancestral CNE repertoire through both extreme divergence and de novo emergence. Finally, we support newly identified pan-teleost CNEs have potential for accurate resolution of teleost phylogenetic placements in par with coding sequences, unlike ancestral only elements shared with spotted gar. This work provides new insight into CNE evolution with great value for follow-up work on phylogenomics, comparative genomics and the study of gene regulation evolution in teleosts.

genomics↗

bioRxiv2023

Co-inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription

Pancreatic carcinoma is one of the most lethal cancers and the absence of efficient therapeutic strategies results in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC impacts initiation, development, and survival of this tumor type. Using patient-derived xenografts of pancreatic carcinoma driven by KRAS and MYC oncogenic transcription, we show that co-inhibition of Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) synergistically induce tumor regression through targeting promoter pause-release, a rate-limiting step in transcription elongation. By comparing the nascent transcriptome with the recruitment of elongation and termination factors along genes, we found that co-inhibition of TOP1 and BRD4, while globally impairing RNA production, disturbs recruitment of proteins involved in termination. Thus, RNA polymerases continue transcribing downstream of genes for hundreds of kilobases leading to readthrough transcription. This pervasive transcription also occurs during replication, perturbing replisome progression and leading to DNA damage. The synergistic effect of TOP1 and BRD4 inhibition is specific for cancer cells leaving normal cells unharmed, highlighting the sensitivity of the tumor to these transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of high transcription and replication. One Sentence SummaryTOP1 and BRD4 inhibitors synergize to selectively kill pancreatic cancer in vivo via readthrough transcription without emergence of drug resistance

cancer biology↗