A5026778626- Pancreatic and Hepatic Oncology Research
- Cancer Genomics and Diagnostics
- Neuroendocrine Tumor Research Advances
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Chromatin Remodeling and Cancer
- Protein Degradation and Inhibitors
- Signaling Pathways in Disease
- Pancreatic function and diabetes
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Lung Cancer Research Studies
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Histone Deacetylase Inhibitors Research
- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Graphene and Nanomaterials Applications
- DNA Repair Mechanisms
- Cancer-related gene regulation
- Bone Metabolism and Diseases
- RNA Research and Splicing
- Genetics, Aging, and Longevity in Model Organisms
- Neuroblastoma Research and Treatments
- Telomeres, Telomerase, and Senescence
Robert Bosch Hospital
2023-2025
Universitätsmedizin Göttingen
2012-2023
Robert Bosch (Netherlands)
2023
University of Göttingen
2014-2020
Mayo Clinic in Florida
2020
WinnMed
2020
Nephrologisches Zentrum Goettingen
2020
University Medical Center
2019
University Medical Center Hamburg-Eppendorf
2012-2014
Universität Hamburg
2012-2014
Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 ΔNp63, respectively. Objective This study sought to uncover transcriptional regulatory mechanisms controlling PDAC subtype identity. Design We integrated primary tumour single-cell RNA-seq, patient-derived xenograft RNA-seq multispectral imaging identify...
The estrogen receptor α (ERα) controls cell proliferation and tumorigenesis by recruiting various cofactors to response elements (EREs) control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ERα-dependent cancers. We show that BRD4 regulates ERα-induced expression affecting elongation-associated phosphorylation RNA polymerase II (RNAPII) histone H2B monoubiquitination. Consistently, activity is required ER+ breast...
Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control the transcription defined subsets genes in various systems. In this study we examined role BRD4 promoting lineage-specific show that osteoblast differentiation. Genome-wide analyses demonstrate recruited transcriptional start site differentiation-induced genes. Unexpectedly, while...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role this study, we investigated the effects of class I-specific HDAC inhibitor (HDACi) 4SC-202 multiple PDAC cell lines promoting tumor differentiation. We show that...
Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, DNA repair. Recent studies have uncovered role for DOT1L the initiation progression leukemia other solid tumors. The development availability small molecule inhibitors may provide...
Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because this association, it commonly assumed H2Bub1 an exclusively positively acting and increased occupancy correlates with gene expression. In contrast, depletion the ubiquitin ligases RNF20 or RNF40 alters expression only subset genes. Using conditional Rnf40 knockout mouse embryo fibroblasts, we show genes occupied by low moderate amounts are selectively...
Targeting the Mdm2 oncoprotein by drugs has potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited simultaneously a second negative regulator p53, phosphatase Wip1/PPM1D. When combining Nutlin-3a with Wip1 inhibitor GSK2830371 in treatment p53-proficient but not p53-deficient cells, observed enhanced phosphorylation (Ser 15)...
The coordinated temporal and spatial activation of gene expression is essential for proper stem cell differentiation. Chromodomain Helicase DNA-binding protein 1 (CHD1) a chromatin remodeler closely associated with transcription nucleosome turnover downstream the transcriptional start site (TSS). In this study, we show that CHD1 required induction osteoblast-specific expression, extracellular-matrix mineralization ectopic bone formation in vivo. Genome-wide occupancy analyses revealed...
Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family epigenetic readers which under intensive investigation as target for anti-tumor therapy. BRD4 plays central role in promoting expression select subsets genes including many driven by oncogenic transcription factors signaling pathways. However, effects BET inhibitors non-transformed cells remain mostly unclear. We demonstrate that required maintenance basal epithelial phenotype...
Abstract The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, inhibitors to both targets approved or clinically tested for therapy. However, we show that of antagonize each other their cytotoxicity towards sarcoma cells. inhibition attenuates the induction p53-responsive upon inhibition. Moreover, p53 response was also attenuated when co-depleting with siRNA, compared single knockdown. complexes MDM2, as well Cyclin D1, physically associated other, suggesting direct...
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis the consequences pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases numbers pre-, immature mature B while early pro-B remain constant. In addition, increases apoptosis T cells, all together leading to reduced cellularity thymus, bone marrow spleen....
Polycomb Repressive Complex 2 (PRC2) is a key regulator of chromatin architecture and transcriptional repression, playing essential roles in development disease. While its enzymatic activity well characterized, the molecular factors governing PRC2 subnuclear organization, particularly cancer cells, are largely unknown. Here, we integrate high-resolution situ spatial proteomics, imaging, functional genomics to investigate compartmentalization triple-negative breast (TNBC) cells. We identify...
To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) primary patient-derived cancer cells. We show that have higher longer telomeres than bulk tumor Inhibition activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted marker depletion, abrogation formation vitro reduced tumorigenicity vivo. Furthermore, identify a positive feedback loop between stemness factors...
Abstract Pancreatic ductal adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited gemcitabine alone in combination other drugs. While resistance has been widely attributed the levels of one its targets, RRM1, molecular consequences PDAC remain largely elusive. Here we sought identify genomic, epigenomic, transcriptomic events associated their...
Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In study, we aimed to identify novel mechanistic approaches overcome or prevent resistance in PDAC.We used vitro vivo models of resistant PDAC integrated epigenomic, transcriptomic, nascent RNA chromatin topology data. We identified JunD-driven subgroup enhancers, called interactive hubs (iHUBs),...
Abstract Physical activity‐induced mechanical stimuli play a crucial role in preserving bone mass and structure by promoting formation. While the Wnt pathway is pivotal for mediating osteoblast response to loading, exact mechanisms are not fully understood. Here, we found that stimulation induces osteoblastic Wnt1 expression, resulting an upregulation of key osteogenic marker genes, including Runx2 Sp7 , while knockdown using siRNA prevented these effects. RNAseq analysis identified Plat as...
Abstract Aim Tieg1 is involved in multiple signalling pathways, human diseases, and highly expressed muscle where its functions are poorly understood. Methods We have utilized knockout (KO) mice to identify novel important roles for this transcription factor regulating ultrastructure, metabolism mitochondrial the soleus extensor digitorum longus (EDL) muscles. RNA sequencing, immunoblotting, transmission electron microscopy, MRI, NMR, histochemical function assays were performed. Results...
Abstract A major hurdle to the application of precision oncology in pancreatic cancer is lack molecular stratification approaches and targeted therapy for defined subtypes. In this work, we sought gain further insight identify epigenetic signatures Basal-like ductal adenocarcinoma (PDAC) subgroup that can be applied clinical samples patient and/or monitoring. We generated integrated global gene expression epigenome mapping data from patient-derived xenograft models subtype-specific enhancer...
Abstract The CRISPR/Cas9 technology has revolutionized genotype-to-phenotype assignments through large-scale loss-of-function (LOF) screens. However, limitations like editing inefficiencies and unperturbed genes cause significant noise in data collection. To address this, we introduce CRISPR Gene Transcriptome Engineering (CRISPRgate), which uses two specific sgRNAs to simultaneously repress cleave the target gene within same cell, increasing LOF efficiencies reproducibility. CRISPRgate...
<div>Abstract<p>A major hurdle to the application of precision oncology in pancreatic cancer is lack molecular stratification approaches and targeted therapy for defined subtypes. In this work, we sought gain further insight identify epigenetic signatures basal-like A ductal adenocarcinoma (PDAC) subgroup that can be applied clinical samples patient and/or monitoring. We generated integrated global gene expression epigenome mapping data from patient-derived xenograft (PDX) models...
<p>Defining the basal-like A-specific enhancer landscape in PDAC</p>