RESUMO
BACKGROUND: Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized. RESULTS: Here we measure changes in the spatial chromatin conformation in mouse liver using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription. We find topologically associating domains harboring circadian genes that switch assignments between the transcriptionally active and inactive compartment at different hours of the day, while their boundaries stably maintain their structure over time. To study chromatin contacts of promoters at high resolution over time, we apply promoter capture Hi-C. We find circadian gene promoters displayed a maximal number of chromatin contacts at the time of their peak transcriptional output. Furthermore, circadian genes, as well as contacted and transcribed regulatory elements, reach maximal expression at the same timepoints. Anchor sites of circadian gene promoter loops are enriched in DNA binding sites for liver nuclear receptors and other transcription factors, some exclusively present in either rhythmic or stable contacts. Finally, by comparing the interaction profiles between core clock and output circadian genes, we show that core clock interactomes are more dynamic compared to output circadian genes. CONCLUSION: Our results identify chromatin conformation dynamics at different scales that parallel oscillatory gene expression and characterize the repertoire of regulatory elements that control circadian gene transcription through rhythmic or stable chromatin configurations.
Assuntos
Ritmo Circadiano/genética , Genoma , Regiões Promotoras Genéticas , Animais , Sequência de Bases , Relógios Biológicos/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Genéticos , Fatores de Tempo , Transcrição GênicaRESUMO
Heterochromatin is a constituent of eukaryotic genomes with functions spanning from gene expression silencing to constraining DNA replication and repair. Inside the nucleus, heterochromatin segregates spatially from euchromatin and is localized preferentially toward the nuclear periphery and surrounding the nucleolus. Despite being an abundant nuclear compartment, little is known about how heterochromatin regulates and participates in the mechanisms driving genome organization. Here, we review pioneer and recent evidence that explores the functional role of heterochromatin in the formation of distinct chromatin compartments and how failure of the molecular mechanisms forming heterochromatin leads to disarray of genome conformation and disease.