ABSTRACT
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Subject(s)
Carcinoma, Hepatocellular/genetics , DNA-Binding Proteins/genetics , Liver Neoplasms/genetics , Nuclear Proteins/genetics , Oncogenes/genetics , Animals , Blotting, Western , Carcinogenesis/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Neoplasm Metastasis , Nuclear Proteins/metabolism , RNA Interference , Transcription FactorsABSTRACT
Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury.
Subject(s)
DNA-Binding Proteins/metabolism , Liver Regeneration , Liver/metabolism , Nuclear Proteins/metabolism , Animals , Cell Differentiation , Cell Proliferation , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Liver/cytology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Transcription FactorsABSTRACT
Many animals, including humans, select alternate forms of motion (gaits) to move efficiently in different environments. However, it is unclear whether primitive animals, such as nematodes, also use this strategy. We used a multifaceted approach to study how the nematode Caenorhabditis elegans freely moves into and out of water. We demonstrate that C. elegans uses biogenic amines to switch between distinct crawling and swimming gaits. Dopamine is necessary and sufficient to initiate and maintain crawling after swimming. Serotonin is necessary and sufficient to transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. Further study of locomotory switching in C. elegans and its dependence on biogenic amines may provide insight into how gait transitions are performed in other animals.
Subject(s)
Caenorhabditis elegans/physiology , Dopamine/physiology , Locomotion/physiology , Serotonin/physiology , Animals , Animals, Genetically Modified , Behavior, Animal/physiology , Biomechanical Phenomena , Dopaminergic Neurons/physiology , Gait/physiology , Serotonergic Neurons/physiology , Signal Transduction/physiology , Swimming/physiology , Video Recording , Viscosity , WaterABSTRACT
Low doses of ethanol cause flies to become hyperactive, while high doses are sedating. The sensitivity to ethanol-induced sedation of a given fly strain is correlated with that strain s ethanol preference, and therefore sedation is a highly relevant measure to study the genetics of alcohol responses and drinking. We demonstrate a simple way to expose flies to ethanol and measure its intoxicating effects. The assay we describe can determine acute sensitivity, as well as ethanol tolerance induced by repeat exposure. It does not require a technically involved setup, and can therefore be applied in any laboratory with basic fly culture tools.