A5040870244- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Acute Myeloid Leukemia Research
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Advanced biosensing and bioanalysis techniques
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Nuclear Structure and Function
- interferon and immune responses
- Pluripotent Stem Cells Research
- CAR-T cell therapy research
- Chronic Lymphocytic Leukemia Research
- Acute Lymphoblastic Leukemia research
- Cancer Genomics and Diagnostics
- Phagocytosis and Immune Regulation
- Renal and related cancers
- Retinoids in leukemia and cellular processes
- Genetics, Aging, and Longevity in Model Organisms
- Genetics and Neurodevelopmental Disorders
- Endoplasmic Reticulum Stress and Disease
- Cell death mechanisms and regulation
- Viral Infectious Diseases and Gene Expression in Insects
Twist Bioscience (United States)
2024
Research Institute of Molecular Pathology
2014-2023
Vienna Biocenter
2015-2023
Cancer Research UK Manchester Institute
2014
University of Manchester
2014
Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing RNA], a method quantification newly synthesized messenger RNAs (mRNAs), with pharmacological chemical-genetic perturbation order define functions two transcriptional hubs cancer, BRD4 MYC, interrogate responses BET bromodomain inhibitors (BETis). found that acts as general coactivator...
Eukaryotic cells store their chromosomes in a single nucleus. This is important to maintain genomic integrity, as packaged into separate nuclei (micronuclei) are prone massive DNA damage. During mitosis, higher eukaryotes disassemble nucleus and release individualized for segregation. How numerous subsequently reform has remained unclear. Using image-based screening of human cells, we identified barrier-to-autointegration factor (BAF) key guiding membranes form Unexpectedly, nuclear assembly...
Recent genome analyses have identified recurrent mutations in the cohesin complex a wide range of human cancers. Here we demonstrate that most frequently mutated subunit complex, STAG2, displays strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion STAG2 but not wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. inactivation inhibits proliferation bladder cancer Ewing sarcoma lines....
Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation undifferentiated lymphoblasts. Although mutation is critical driver B-ALL development mice and humans, it remains unclear how its loss contributes to leukemogenesis whether ongoing deficiency required for maintenance. Here we used transgenic RNAi reversibly suppress endogenous Pax5 expression...
The transcriptional repressors Polycomb repressive complex 1 (PRC1) and PRC2 are required to maintain cell fate during embryonic development. PRC1 catalyze distinct histone modifications, establishing chromatin at shared targets. How PRC1, which consists of canonical (cPRC1) variant (vPRC1) complexes, cooperate silence genes support mouse stem (mESC) self-renewal is unclear. Using combinatorial genetic perturbations, we show that independent pathways cPRC1 vPRC1 responsible for maintenance...
Abstract Genomic imprinting is regulated by parental-specific DNA methylation of control regions (ICRs). Despite an identical sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic determinants this bistability. By iterative integration related sequences to ectopic location mouse genome, first identify sequence features required for maintenance embryonic...
MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity C-terminal fusion partners MLL. While studies selected have revealed critical pathways, unifying mechanisms across all remain poorly understood. We present first comprehensive survey protein-protein interactions seven distantly related MLL-fusion proteins. Functional investigation 128 conserved MLL-fusion-interactors identifies specific role for lysine methyltransferase...
The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed synthetic lethal interaction between and its paralog STAG1 . To systematically probe genetic vulnerabilities the absence of STAG2, we performed genome-wide CRISPR screens isogenic cell lines identified most prominent selective dependency STAG2-deficient cells. an inducible degron system, show that chemical degradation protein results...
// Stefanie Schlager 1 , Carina Salomon Sabine Olt Christoph Albrecht Anja Ebert 2 Oliver Bergner Johannes Wachter Francesca Trapani Daniel Gerlach Tilman Voss Anna Traunbauer Julian Jude Matthias Hinterndorfer Martina Minnich Norbert Schweifer Sophia M. Blake 3 Vittoria Zinzalla Barbara Drobits Darryl B. McConnell Kraut Mark Pearson Zuber 4 and Manfred Koegl Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC),...
Ricin is one of the most feared bioweapons in world due to its extreme toxicity and easy access. Since no antidote exists, it paramount importance identify pathways underlying ricin toxicity. Here, we demonstrate that Golgi GDP-fucose transporter Slc35c1 fucosyltransferase Fut9 are key regulators Genetic pharmacological inhibition fucosylation renders diverse cell types resistant via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency also ricin....
Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation these response proteins after pathogen clearance likewise key preventing autoimmunity. Interferon regulatory factor 1 (IRF1) plays an role as a transcription in driving expression immune genes infection. The striking difference output with other IRFs that IRF1 also drives various cell cycle inhibiting factors, making it important tumor suppressor. Thus, critical regulate...
Plasma cells (PCs) and their progenitors plasmablasts (PBs) are essential for the acute long-term protection of host against infections by providing vast levels highly specific antibodies. Several transcription factors, like Blimp1 Irf4, already known to be PC PB differentiation survival. We set out identify additional genes, that development CRISPR-Cas9 screening 3,000 genes loss PBs employing in vitro -inducible germinal center B cell (iGB) culture system Rosa26 Cas9/+ mice. Identified...
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...
Background: Chromosomal rearrangements leading to overexpression of EVI1 (MECOM) on chromosome 3q26 define a distinct subtype acute myeloid leukemia (AML) that is associated with chemotherapy resistance and 2-year survival <10%. While genetic events driving aberrant expression are increasingly understood, the molecular functions drive leukemogenesis unclear, which has so far precluded development targeted therapeutics. Aims: We aimed elucidate transcriptional programs maintained by...
Abstract Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation these response proteins after pathogen clearance likewise key preventing autoimmunity. Interferon Regulatory Factor 1 (IRF1) plays an role as a transcription factor in driving expression immune genes infection. The striking difference output with other IRFs, that IRF1 also drives various cell cycle inhibiting factors, making it important tumor suppressor. Thus,...