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Comparative global methylation profile in DMS114 cells before and after acquired resistance to PD173074

ABSTRACT: Comparative global methylation profile in DMS114 cells before and after acquired resistance to PD173074

PROVIDER: PRJNA475993 | ENA |

REPOSITORIES: ENA

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Comparative global methylation profile in DMS114 cells before and after acquired resistance to PD173074

Project description:The development of acquired resistance (AR) to tyrosine kinase inhibitors (TKIs) of FGFR1 activation is currently not well understood. To gain a deeper insight into this matter in lung cancer, we used the FGFR1-amplified DMS114 cell line and generated multiple clones with AR to an FGFR1-TKI. We molecularly scrutinized the resistant cells, using whole-exome sequencing, RNA sequencing and global DNA methylation analysis. Our results show a de novo activation of AKT and ERK, and a reactivation of mTOR. Furthermore, the resistant cells exhibited strong upregulation and activation of MET, indicating crosstalk between the FGFR1 and MET axes. The resistant cells also underwent a global decrease in promoter hypermethylation of the CpG islands. Finally, we observed clonal expansion of a pre-existing change in AKT1, leading to S266L substitution, within the kinase domain of AKT. Our results demonstrate that AR to FGFR1-TKI involves deep molecular changes that promote the activation of MET and AKT, coupled with common gene expression and DNA methylation profiles. The expansion of a substitution at AKT was the only shared genetic change, and this may have contributed to the AR.

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Project description:Progeny of heavily diseased plants develop transgenerational acquired resistance (TAR). In Arabidopsis, TAR can be transmitted over one stress-free generation. Although DNA methylation has been implicated in the regulation of TAR, the relationship between TAR and global DNA methylation remains unknown. Here, we characterised the methylome of TAR-expressing Arabidopsis at different generations after disease exposure. Global clustering of cytosine methylation revealed TAR-related patterns in the F3 generation, but not in the F1 generation. The majority of differentially methylated positions (DMPs) occurred at CG context in gene bodies. TAR in F3 progeny after one initial generation of disease, followed by two stress-free generations, was lower than TAR in F3 progeny after three successive generations of disease. This difference in TAR effectiveness was proportional to the intensity of differential methylation at a sub-set of cytosine positions. Comparison of TAR-related DMPs with previously characterised cytosine methylation in mutation accumulation lines revealed that ancestral disease stress preferentially acts on methylation-labile cytosine positions, but also extends to methylation-stable positions. Thus, the TAR-related impact of ancestral disease extends beyond stochastic variation in DNA methylation. Our study has shown that the Arabidopsis epigenome responds globally to disease in previous generations and we discuss its contribution to TAR.

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