RESUMO
Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of 'early sentinel' response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
Assuntos
Colite/genética , DNA/genética , Epigênese Genética , Microbioma Gastrointestinal/fisiologia , Genoma , Simbiose/genética , Animais , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colo/metabolismo , Colo/microbiologia , DNA/metabolismo , Metilação de DNA , Sulfato de Dextrana/administração & dosagem , Vida Livre de Germes , Homeostase/genética , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sequenciamento Completo do GenomaRESUMO
Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation.
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Colite/genética , Neoplasias Colorretais/genética , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenoma/imunologia , Adenoma/metabolismo , Animais , Colite/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Metilação de DNA , Epigênese Genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BLRESUMO
AIMS: To document benzodiazepines and antipsychotics (BDZ/APS) given to patients in the last 24 hours of life to establish normal prescribing patterns in hospices across New Zealand (NZ). METHODS: A cross-sectional benchmarking design with retrospective chart review was carried out across 14 NZ hospices. Data (n=351) on medication use and dosages was analysed for inter-hospice variability. Analysis was shared with participating hospices for reflection. RESULTS: There are significant differences in how these predominantly sedative medications are used within hospices in NZ, though the reasons for this cannot be commented on in this study. Diagnosis, place of death and use of the Liverpool Care Pathway influence how medications are used. CONCLUSION: NZ hospices are willing to submit data to enable the description of usual medication use in NZ, and have established that variations in prescribing and administration exist. This enables self reflection on the variations and the establishment of an ongoing benchmarking exercise.
