Gates, K. | Search bioRxiv

bioRxiv2020

Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

Epidermal growth factor receptor inhibitors (EGFRi) are standard-of-care treatments administered to patients with non-small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance within a year post-treatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, mechanisms involved in bypass track activation are understudied, and in a subset of cases the mechanisms are unknown. The findings from this study identified an epigenetic factor, SUV420H2 that when lost drives resistance of NSCLC to multiple EGFRi, including erlotinib, gefitinib, afatinib, and osimertinib. SUV420H2 catalyzes trimethylation of histone H4 lysine-20, a modification required for gene repression and maintenance of heterochromatin. Here we show that loss of SUV420H2 leads to upregulation of an oncogenic long non-coding RNA, LINC01510 that promotes transcription of the oncogene MET, a component of a major bypass track involved in EGFRi resistance. SignificanceDue to an incomplete understanding of the mechanisms involved in promoting resistance to EGFRi, patients often succumb to their disease. Here we identified a global mediator of EGFRi resistance, SUV420H2 that helps to uncover an additional mechanism involved in resistance driven via a major bypass track involving the protooncogene MET.

cancer biology↗

bioRxiv2019

Adaptation of plasticity to predicted climates in Australian rainbowfishes (Melanotaenia) across climatically defined bioregions

Resilience to environmental stressors due to climate warming is influenced by local adaptations, including the capacity for plastic responses. The recent literature has focussed on genomic signatures of climatic adaptation, however little work has been done to address how plastic capacity may be influenced by biogeographic history and evolutionary processes. Here, we investigate phenotypic plasticity as a target of climatic selection, hypothesising that lineages that evolved under warmer climate will exhibit greater plastic adaptive resilience to thermal stress. This was tested using common garden experiments to compare gene expression regulation within and among a temperate, a subtropical and a desert ecotype of Australian rainbowfish. Individuals from each ecotype were subjected to contemporary and projected summer thermal conditions for 2070, and their global patterns of gene expression were characterized using liver transcriptomes. Critical thermal maximums were also determined for each ecotype to assess thermal tolerance. A comparative phylogenetic expression variance and evolution model framework was used to assess plastic and evolved changes in gene expression. Similar changes in both the direction and the magnitude of expressed genes were found within ecotypes. Although most expressed genes were identified in all ecotypes, 532 genes were identified as candidates subject to ecotype-specific directional selection. Twenty-three of those genes showed signal of adaptive (i.e. genetic-based) plastic response to future increases in temperature. Network analyses demonstrated centrality of these genes in thermal response pathways, along with several highly conserved hub genes thought to be integral for heat stress responses. The greatest adaptive resilience to warming was shown by the subtropical ecotype, followed by the desert and temperate ecotypes. Our findings indicate that vulnerability to climate change will be highly influenced by biogeographic factors, and we stress the need for integrative assessments of climatic adaptive traits for accurate estimations of population and ecosystem responses.

ecology↗