Biology subjects

Drablos, F.

Publications and source records attributed to Drablos, F..

6 recordsLinked to original sources

bioRxiv2022

FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer

Mitochondrial activity in cancer cells has been central to cancer research since Otto Warburg first published his thesis on the topic in 1956. Although Warburg proposed that oxidative phosphorylation in the tricarboxylic acid (TCA) cycle was perturbed in cancer, later research has shown that oxidative phosphorylation is activated in most cancers, including prostate cancer (PCa). However, more detailed knowledge on mitochondrial metabolism and metabolic pathways in cancers is still lacking. In this study we expand our previously developed method for analyzing functional homologous proteins (FunHoP), which can provide a more detailed view of metabolic pathways. FunHoP uses results from differential expression analysis of RNA-Seq data to improve pathway analysis. By adding information on subcellular localization based on experimental data and computational predictions we can use FunHoP to differentiate between mitochondrial and non-mitochondrial processes in cancerous and normal prostate cell lines. Our results show that mitochondrial pathways are upregulated in PCa and that splitting metabolic pathways into mitochondrial and non-mitochondrial counterparts using FunHoP adds to the interpretation of the metabolic properties of PCa cells.

bioinformatics↗

bioRxiv2022

Where Honey Bee Vitellogenin may Bind Zn2+-Ions

The protein Vitellogenin (Vg) plays a central role in lipid transportation in most egg-laying animals. High Vg levels correlate with stress resistance and lifespan potential in honey bees (Apis mellifera). Vg is the primary circulating zinc-carrying protein in honey bees. Zinc is an essential metal ion in numerous biological processes, including the function and structure of many proteins. Measurements of Zn2+ suggest a variable number of ions per Vg molecule in different animal species, but the molecular implications of zinc-binding by this protein are not well understood. We used inductively coupled plasma mass spectrometry (ICP-MS) to determine that, on average, each honey bee Vg molecule binds 3 Zn2+-ions. Our full-length protein structure and sequence analysis revealed seven potential zinc-binding sites. These are located in the {beta}-barrel and -helical subdomains of the N-terminal domain, the lipid binding site, and the cysteine-rich C-terminal region of unknown function. Interestingly, two potential zinc-binding sites in the {beta}-barrel can support a proposed role for this structure in DNA-binding. Overall, our findings illustrate the capacity of honey bee Vg to bind zinc at several functional regions, indicating that Zn2+-ions are important for many of the activities of this protein. In addition to being potentially relevant for other egg-laying species, these insights provide a platform for studies of metal ions in bee health, which is of global interest due to recent declines in pollinator numbers.

biochemistry↗

bioRxiv2021

The genes controlling normal function of citrate and spermine secretion is lost in aggressive prostate cancer and prostate model systems

BackgroundSecretion of the metabolites citrate and spermine into prostate lumen is a unique hallmark for normal prostate epithelial cells. However, the identity of the genes controlling citrate and spermine secretion remains mostly unknown despite their obvious relevance for progression to aggressive prostate cancer. Materials & MethodsIn this study, we have correlated simultaneous measurement of citrate/spermine and transcriptomics data. We have refined these gene correlations in 12 prostate cancer cohorts containing 2915 tissue samples to create a novel gene signature of 150 genes connected with citrate and spermine secretion. We further explored the signature in public data, interrogating over 18 000 samples from various tissues and model systems, including 3826 samples from prostate and prostate cancer. ResultsIn prostate cancer, the expression of this gene signature is gradually lost in tissue from normal epithelial cells through PIN, low grade (Gleason <= 7), high grade cancer (Gleason >= 8) and metastatic lesions. The accuracy of the signature is validated by its unique enrichment in prostate compared to other tissues, and its strong enrichment in epithelial tissue compartments compared to stroma. Several zinc-binding proteins that are not previously investigated in the prostate are present in the gene signature, suggesting new mechanisms for controlling zinc homeostasis in citrate/spermine secretion. However, the absence of the gene signature in all common prostate normal and cancer cell-lines, as well as prostate organoids, underlines the challenge to study the role of these genes during prostate cancer progression in model systems. ConclusionsA large collection of transcriptomics data integrated with metabolomics identifies the genes related to citrate and spermine secretion in the prostate, and show that the expression of these genes gradually decreases on the path towards aggressive prostate cancer. In addition, the study questions the relevance of currently available model systems to study metabolism in prostate cancer development.

bioinformatics↗

bioRxiv2020

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.

developmental biology↗

bioRxiv2018

MACPET: Model-based Analysis for ChIA-PET

We present Model-based Analysis for ChIA-PET (MACPET) which analyzes paired-end read sequences provided by ChIA-PET for finding binding sites of a protein of interest. MACPET uses information from both tags of each PET and searches for binding sites in a two-dimensional space, while taking into account different noise levels in different genomic regions. MACPET shows favorable results compared to MACS in terms of motif occurrence, spatial resolution and false discovery rate. Significant binding sites discovered by MACPET are involved in a higher number of significant 3D interactions than those discovered by MACS. MACPET is freely available on Bioconductor.

bioinformatics↗

bioRxiv2017

Cholesterol Synthesis Pathway Genes in Prostate Cancer are consistently downregulated when tissue confounding is minimized.

The relationship between cholesterol and prostate cancer has been extensively studied for decades, where high levels of cellular cholesterol are generally associated with cancer progression and less favorable outcomes. However, the role of in vivo cellular cholesterol synthesis in this process is unclear, and data on the transcriptional activity of cholesterol synthesis pathway genes in tissue from prostate cancer patients are inconsistent. A common problem with cancer tissue data from patient cohorts is the presence of heterogeneous tissue which confounds molecular analysis of the samples. In this study we present a method to minimize systematic confounding from stroma tissue in seven patient cohorts consisting of 1713 prostate cancer and 230 normal tissue samples. When confounding was minimized, differential gene expression analysis over all cohorts showed robust and consistent downregulation of nearly all genes in the cholesterol synthesis pathway. Additional analysis also identified cholesterol synthesis as the most significantly altered metabolic pathway in prostate cancer. This surprising observation is important for our understanding of how prostate cancer cells regulate cholesterol levels in vivo. Moreover, we show that tissue heterogeneity explains the lack of consistency in previous expression analysis of cholesterol synthesis genes in prostate cancer.

cancer biology↗