Reynes, C. | bioRxiv Science

bioRxiv2019

Ubiquitin and SUMO conjugation as biomarkers of Acute Myeloid Leukemias response to chemotherapies

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cells response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict Acute Myeloid Leukemias (AML) response to standard chemotherapy (daunorubicine-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9000 proteins spotted on protein-arrays. We identified 122 proteins whose conjugation by these post-translational modifiers marks AML resistance to DNR and/or Ara-C. Based on this modifomic signature, we defined a statistical score able to predict AML patient response to standard chemotherapy. We finally developed a miniaturized assay to easily assess the modification level of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patients response to treatments.\n\nSummary blurbThis study describes the identification of a new class of biomarkers of cancer response to therapies based on protein modification by Ubiquitin and SUMO and provides the tools to analyze them in Acute Myeloid Leukemia patient samples.

cancer biology↗

bioRxiv2018

Lost in translation: egg transcriptome reveals molecular signature to predict developmental success and novel maternal-effect genes

BackgroundGood quality or developmentally competent eggs result in high survival of progeny. Previous research has shed light on factors that determine egg quality, however, large gaps remain. Initial development of the embryo relies on maternally-inherited molecules, such as transcripts, deposited in the egg, thus, they would likely reflect egg quality. We performed transcriptome analysis on zebrafish fertilized eggs of different quality from unrelated, wildtype couples to obtain a global portrait of the egg transcriptome to determine its association with developmental competence and to identify new candidate maternal-effect genes.\n\nResultsFifteen of the most differentially expressed genes (DEGs) were validated by quantitative real-time PCR. Gene ontology analysis showed that enriched terms included ribosomes and translation. In addition, statistical modeling using partial least squares regression and genetics algorithm also demonstrated that gene signatures from the transcriptomic data can be used to predict reproductive success. Among the validated DEGs, otulina and slc29a1a were found to be increased in good quality eggs and to be predominantly localized in the ovaries. CRISPR/Cas9 knockout mutants of each gene revealed remarkable subfertility whereby the majority of their embryos were unfertilizable. The Wnt pathway appeared to be dysregulated in the otulina knockout-derived eggs.\n\nConclusionsOur novel findings suggested that even in varying quality of eggs due to heterogeneous causes from unrelated wildtype couples, gene signatures exist in the egg transcriptome, which can be used to predict developmental competence. Further, transcriptomic profiling revealed two new potential maternal-effect genes that have essential roles in vertebrate reproduction.

genomics↗