Biology subjects

Winkler, R.

Publications and source records attributed to Winkler, R..

4 recordsLinked to original sources

bioRxiv2021

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

cancer biology↗

bioRxiv2021

Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet

Hepatocyte nuclear factor 4 (HNF4) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study was aimed to elucidate the role of down-regulation of HNF4 and GR in fatty liver and hyperlipidemia. Adult mice with liver-specific heterozygote and knockout (knockout) of HNF4 were fed a low-fat diet (LFD) or a high-fat-high-sugar diet (HFHS) for 15 days. Compared to LFD-fed mice, HFHS-fed wildtype mice had hepatic induction of lipid catabolic genes and down-regulation of lipogenic genes. Compared to HFHS-fed wildtype mice, HNF4 heterozygote mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4 knockout mice had mild hypolipidemia, down-regulation of lipid-efflux genes, but induction of genes for uptake/storage of lipids. Sterol-regulatory-element-binding protein-1c (SREBP-1C), a master lipogenic regulator, was induced in HFHS-fed HNF4 heterozygote mice. In reporter assays, HNF4 potently inhibited the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Surprisingly, nuclear GR proteins were gene-dosage-dependently decreased in HNF4 heterozygote and knockout mice. HFHS-fed mice with liver-specific knockout of GR had increased hepatic lipids and induction of SREBP-1C and PPAR{gamma}. In reporter assays, GR and HNF4 synergistically/additively induced lipid catabolic genes. Phosphorylation of AMP-activated protein kinase (AMPK), a key GR modulator, was dramatically decreased in HNF4 knockout mice. Thus, cooperative induction of lipid catabolic genes and suppression of lipogenic genes by HNF4 and GR, modulated by AMPK, may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.

molecular biology↗

bioRxiv2020

SARS-CoV-2 utilizes a multipronged strategy to suppress host protein synthesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. Here, we use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show SARS-CoV-2 infection leads to a global reduction in translation but that viral transcripts are not preferentially translated. Instead, we reveal that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we show that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.

microbiology↗

bioRxiv2020

Target-Decoy MineR for determining the biological relevance of variables in noisy data sets

Machine learning algorithms excavate important variables from biological big data. However, deciding on the biological relevance of identified variables is challenging. The addition of artificial noise, decoy variables, to raw data, target variables, enables calculating a false-positive rate (FPR) and a biological relevance probability (BRp) for each variable rank. These scores allow the setting of a cut-off for informative variables can be defined, depending on the required sensitivity/ specificity of a scientific question. We demonstrate the function of the Target-Decoy MineR (TDM) with synthetic data and with experimental metabolomics results. The Target-Decoy MineR is suitable for different types of quantitative data in tabular format. An implementation of the algorithm in R is freely available from https://bitbucket.org/cesaremov/targetdecoy_mining/.

bioinformatics↗