A5053990627- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Histone Deacetylase Inhibitors Research
- Acute Myeloid Leukemia Research
- Cancer Cells and Metastasis
- Neonatal Respiratory Health Research
- Genomics and Chromatin Dynamics
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Acute Lymphoblastic Leukemia research
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- Renal and related cancers
- Histiocytic Disorders and Treatments
- Sarcoma Diagnosis and Treatment
- Chronic Myeloid Leukemia Treatments
- Bone Tumor Diagnosis and Treatments
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Congenital Diaphragmatic Hernia Studies
- PARP inhibition in cancer therapy
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Genetic Syndromes and Imprinting
- Developmental Biology and Gene Regulation
German Cancer Research Center
2019-2025
Heidelberg University
2019-2025
Epigenomics (Germany)
2019-2025
German Center for Lung Research
2022
Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by de-repression endogenous retroviral element (ERV)-encoded promoters, and initiation transcription. Here, we use deep RNA sequencing from cell lines treated DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase (HDACi), to assemble a de novo transcriptome identify several thousand...
Abstract Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of mucostatic microenvironment epigenetic reprogramming macrophages (AM) resulting transcriptomic phenotypical changes. Using a mouse model muco-obstructive lung disease ( Scnn1b -transgenic), identify epigenetically controlled, differentially regulated pathways transcription factors...
Abstract Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated altered epigenetic signaling in lung cells. We generated genome‐wide DNA methylation maps at single CpG resolution of primary human fibroblasts (HLFs) across stages. show the landscape is changed early COPD, changes occurring predominantly regulatory regions. RNA sequencing matched demonstrated...
Abstract The neoplastic stromal cells of giant cell tumor bone (GCTB) carry a mutation in H3F3A , leading to mutant histone variant, H3.3-G34W, as sole recurrent genetic alteration. We show that patient-derived H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on DNA methylation, accessibility modification level, can be partially recapitulated an orthogonal line system by introduction H3.3-G34W. These affect mainly heterochromatic bivalent...
Characterization of adult T-ALL methylomes identifies a clinically aggressive hypermethylated subgroup sensitive to 5-azacytidine.
Abstract Cancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated (CAF). These CAFs are genomically stable, yet transcriptional programs distinct from those of counterparts. Transcriptional regulation plays a major role this reprogramming, but the extent which epigenetic modifications DNA also contribute rewiring CAF transcription is not clear. Here we address question by dissecting landscape breast CAFs. Applying...
Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between break point partners (motor neuron pancreas homeobox 1 [MNX1] ETS variant transcription factor 6 [ETV6]) been reported subset of cases. However, universal feature is strong transcript protein expression MNX1, that normally not expressed hematopoietic cells. Here, we map points on chromosomes 7 12 affected patients to region...
Cancer-associated fibroblasts (CAFs) represent a central cell population of the tumor microenvironment (TME). Recently, single-cell RNA-sequencing (scRNA-seq) analyses primary tumors different cancer entities yielded classifications CAF subsets underscoring heterogeneity CAFs within TME. Here, we analyzed transcriptional signatures approximately 8400 and normal by scRNA-seq compared genetic profiles from murine melanoma to corresponding lung metastases. This revealed distinct for...
The accumulation of myeloid cells, particularly tumor-associated macrophages (TAMs), characterizes the tumor microenvironment (TME) many solid cancers, including breast cancer. Compared to healthy tissue-resident macrophages, TAMs acquire distinct transcriptomes and tumor-promoting functions by largely unknown mechanisms. Here, we hypothesize involvement TME signaling subsequent epigenetic reprogramming TAMs. Using 4T1 mouse model triple-negative cancer, demonstrate that presence cancer...
Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome, such as AML with translocation t(7;12)(q36;p13) leading to an MNX1::ETV6 fusion along high expression MNX1. We identified the transforming event this and possible ways treatment. Retroviral MNX1 was able induce mice, similar gene pathway enrichment t(7;12) patient data. Importantly, only induced immune incompetent mice using fetal but not adult hematopoietic stem progenitor cells. The restriction capacity...
Abstract The high plasticity of lung epithelial cells, has for many years, confounded the correct identification cell-of-origin adenocarcinoma (LUAD), one deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate cell origin Eml4-Alk LUAD, and show that Club Alveolar type 2 (AT2) cells give rise tumours. We focus on originated tumours find experience an epigenetic switch by which they lose their lineage fidelity gain AT2-like phenotype after oncogenic...
The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported ID3 loss associated mutational signatures linked to repair defects. Here we demonstrate exhibits dual role promote double-strand break (DSB) repair, particularly homologous recombination (HR). interacts the MRN complex and RECQL helicase activate DSB it facilitates RAD51 loading downstream steps HR. In...
Abstract The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined decitabine (DAC), all- trans retinoic acid (ATRA) resulted improved longer overall survival randomized phase II trial (DECIDER; NCT00867672). molecular mechanisms governing this vivo synergism are unclear. We now demonstrate...
FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses evolutionary conservation chromatin status Foxn1 locus in different tissues states identified several putative cis-regulatory regions unique to TECs versus HFCs. Furthermore, experiments using genetically modified mice with...
Abstract Motivation Whole-genome bisulfite sequencing (WGBS) measures DNA methylation at base pair resolution resulting in large bedGraph like coverage files. Current options for processing such files are hindered by discrepancies file format specification, speed, and memory requirements. Results We developed methrix, an R package, which provides a toolset systematic analysis of datasets. Core functionality the package includes comprehensive or similar tab-separated text reader—which...
Abstract Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners ( MNX1 ETV6 ) been reported subset of cases. However, universal feature is strong transcript protein expression MNX1, homeobox transcription factor that normally not expressed hematopoietic cells. Here, we map breakpoints on chromosomes 7 12 affected patients to region proximal either introns 1 or...
Abstract Chronic lung diseases, including chronic obstructive pulmonary disease (COPD), affect over 500 million people and are a leading cause of death worldwide. A common feature both acute diseases is altered respiratory barrier integrity impaired regeneration. We hypothesized that alveolar type 2 (AT2) cells, as epithelial progenitors, will carry molecular alterations compromise regeneration in COPD. Sorted AT2 cells from ex-smokers with without COPD at different stages were subjected to...
Targeted analysis of DNA methylation patterns based on bisulfite-treated genomic (BT-DNA) is considered as a gold-standard for epigenetic biomarker development. Existing software tools facilitate primer design, quality control or visualization localization. However, high-throughput design primers BT-DNA amplification hampered by limits in throughput and functionality existing tools, requiring users to repeatedly perform specific tasks manually. Consequently, the PCR remains tedious...
<div>Abstract<p>Cancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated (CAF). These CAFs are genomically stable, yet transcriptional programs distinct from those of counterparts. Transcriptional regulation plays a major role this reprogramming, but the extent which epigenetic modifications DNA also contribute rewiring CAF transcription is not clear. Here we address question by dissecting landscape breast CAFs....
Summary The high plasticity of lung epithelial cells, has for many years, confounded the correct identification cell-of-origin adenocarcinoma (LUAD), one deadliest malignancies worldwide. Here, we address LUAD, by employing lineage-tracing mouse models combined with a CRISPR/Cas9 system to induce an oncogenic Eml4-Alk rearrangement in virtually all cell types lung. We find that Club cells give rise tumours higher frequency than AT2 cells. Based on whole genome methylome, identified retain...
The neoplastic stromal cells of giant cell tumor bone (GCTB) carry a mutation in H3F3A, leading to mutant histone variant, H3.3-G34W, as sole recurrent genetic alteration. We show that patient-derived H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on DNA methylation, accessibility modification level can be partially recapitulated an orthogonal line system by introduction H3.3-G34W. These affect mainly heterochromatic bivalent regions provide...
Abstract Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering the environmental cause of COPD (e.g., cigarette smoke) and phenotypes, including stem-cell senescence impaired differentiation, we hypothesized that will be associated altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution primary human fibroblasts (HLFs) isolated from distal parenchyma ex-smoker controls...