Both, protein arginine methyltransferases (PRMTs) and protein kinases are critical regulators of cellular processes and frequently dysregulated in malignancy. To systematically study the crosstalk of the two regulatory enzyme classes, we used parallel yeast two-hybrid matrix screening and defined 45 interactions connecting 4 PRMTs and 20 human kinases. The PRMT-kinase network revealed a strong association […]
Influenza A infection accelerates disease-associated microglia formation during physiological aging
Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test […]
Cancer pathway connectivity resolved by drug perturbation and RNA sequencing
Pathway inhibitors are a backbone of cancer treatment. The configuration of pathway dependencies varies from tumour to tumour. Better treatment for individual patients could be designed if the pathway wiring were readily measurable. Here, we characterise the transcriptional responses of 116 lymphoma patient samples exposed to ten drug perturbations. We used factor analysis to decompose […]
Discovery of Non-Degradative Covalent Molecular Glues for Transcriptional Reprogramming
Transcriptional reprogramming through induced proximity has emerged as a powerful strategy for modulating the expression of oncogenic and tumor-suppressive genes. Inspired by transcriptional reprogramming approaches such as transcriptional/epigenetic chemical inducers of proximity (TCIPs) that link BCL6 inhibitors to transcriptional regulators, we sought to develop covalent ligands that rewire BCL6 proximity to selectively suppress MYC transcriptional […]
Influenza A infection accelerates disease-associated microglia formation during physiological aging
Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test […]
The cytosolic PRMT5-CDK4 complex impairs cell cycle kinase signaling
Both, protein arginine methyltransferases (PRMTs) and protein kinases are critical regulators of cellular processes and frequently dysregulated in malignancy. To systematically study the crosstalk of the two regulatory enzyme classes, we used parallel yeast two-hybrid matrix screening and defined 45 interactions connecting 4 PRMTs and 20 human kinases. The PRMT-kinase network revealed a strong association […]
Cancer pathway connectivity resolved by drug perturbation and RNA sequencing
Pathway inhibitors are a backbone of cancer treatment. The configuration of pathway dependencies varies from tumour to tumour. Better treatment for individual patients could be designed if the pathway wiring were readily measurable. Here, we characterise the transcriptional responses of 116 lymphoma patient samples exposed to ten drug perturbations. We used factor analysis to decompose […]
Discovery of Non-Degradative Covalent Molecular Glues for Transcriptional Reprogramming
Transcriptional reprogramming through induced proximity has emerged as a powerful strategy for modulating the expression of oncogenic and tumor-suppressive genes. Inspired by transcriptional reprogramming approaches such as transcriptional/epigenetic chemical inducers of proximity (TCIPs) that link BCL6 inhibitors to transcriptional regulators, we sought to develop covalent ligands that rewire BCL6 proximity to selectively suppress MYC transcriptional […]
WRN helicase regulates mitophagy by resolving an intricate nexus of G-quadruplexes-R loops-ATG7 pre-mRNA maturation in cancer
Werner syndrome (WS) is a progeroid and cancer-predisposition disorder caused by loss of the Werner RECQ helicase-exonuclease (WRN), a key genome-maintenance enzyme essential for replication-stress signalling and DNA-repair. WS patients also develop metabolic abnormalities, including fatty-liver and diabetes, suggesting a link between WRN-deficiency and mitochondrial-dysfunction. WRN is frequently epigenetically silenced in cancers, yet its precise […]
Native, full-length, refolding-assisted purification of TDP-43 compatible with BSL-2 safety regulations
TAR DNA-binding protein 43 (TDP-43) is a prion-like RNA-binding protein that plays a key role in amyotrophic lateral sclerosis and frontotemporal dementia. Producing full-length TDP-43 consistently is thus relevant for its in vitro studies and yet it remains challenging, especially with the current requirement to work under biosafety level-2 (BSL-2) containment due to new safety […]