Assuntos
COVID-19/virologia , Receptores Virais/genética , SARS-CoV-2/genética , Fatores de Transcrição/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , COVID-19/genética , COVID-19/metabolismo , Modelos Animais de Doenças , Fatores de Ligação de DNA Eritroide Específicos/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Intestinos/virologia , Camundongos , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo , Proteína Smad4/genética , Glicoproteína da Espícula de Coronavírus/genética , Fatores de Transcrição/metabolismo , Internalização do VírusRESUMO
GATA4 is expressed in the proximal 85% of small intestine where it promotes a proximal intestinal ('jejunal') identity while repressing a distal intestinal ('ileal') identity, but its molecular mechanisms are unclear. Here, we tested the hypothesis that GATA4 promotes a jejunal versus ileal identity in mouse intestine by directly activating and repressing specific subsets of absorptive enterocyte genes by modulating the acetylation of histone H3, lysine 27 (H3K27), a mark of active chromatin, at sites of GATA4 occupancy. Global analysis of mouse jejunal epithelium showed a statistically significant association of GATA4 occupancy with GATA4-regulated genes. Occupancy was equally distributed between down- and up-regulated targets, and occupancy sites showed a dichotomy of unique motif over-representation at down- versus up-regulated genes. H3K27ac enrichment at GATA4-binding loci that mapped to down-regulated genes (activation targets) was elevated, changed little upon conditional Gata4 deletion, and was similar to control ileum, whereas H3K27ac enrichment at GATA4-binding loci that mapped to up-regulated genes (repression targets) was depleted, increased upon conditional Gata4 deletion, and approached H3K27ac enrichment in wild-type control ileum. These data support the hypothesis that GATA4 both activates and represses intestinal genes, and show that GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of H3K27.
Assuntos
Fator de Transcrição GATA4/fisiologia , Histona Acetiltransferases/antagonistas & inibidores , Histonas/metabolismo , Íleo/metabolismo , Acetilação , Animais , Células Cultivadas , Regulação para Baixo/genética , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Intestino Delgado/metabolismo , Lisina/metabolismo , Camundongos , Camundongos TransgênicosRESUMO
The salinity of estuarine environments can vary widely, exposing resident organisms to considerable osmotic stress. The green crab Carcinus maenas is well known for its ability to osmoregulate in response to such stress. Therefore, we tested the relationship between osmoregulation and hemolymph levels of methyl farnesoate (MF), a compound previously shown to rise in response to various types of environmental stresses. When crabs were transferred from 100% seawater to dilute (hypo-osmotic) seawater, hemolymph osmolality dropped rapidly, reaching an acclimation level 48 h after transfer. Hemolymph levels of MF also rose in these animals after a delay of 6 h, and reached a maximum level at 48 h. MF levels remained elevated as long as the crabs were maintained in dilute seawater, and quickly returned to basal levels when the animals were returned to full strength seawater. In most (but not all) animals, MF levels were elevated when hemolymph osmolality fell below the isosmotic point (approx. 800 mOsm/kg). These data suggest that MF may have a role in osmoregulation by this species. In addition, the elevation of MF by hypo-osmotic seawater suggests an experimental strategy for manipulating MF levels in crustaceans.
