The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Funder: FP7 Ideas: European Research Council; doi: http://dx.doi.org/10.13039/100011199; Grant(s): 259743Abstract: 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

Remembering through the genome: the role of chromatin states in brain functions and diseases

Chromatin is the physical substrate of the genome that carries the DNA sequence and ensures its proper functions and regulation in the cell nucleus. While a lot is known about the dynamics of chromatin during programmed cellular processes such as development, the role of chromatin in experience-dependent functions remains not well defined. Accumulating evidence suggests that in brain cells, environmental stimuli can trigger long-lasting changes in chromatin structure and tri-dimensional (3D) organization that can influence future transcriptional programs. This review describes recent findings suggesting that chromatin plays an important role in cellular memory, particularly in the maintenance of traces of prior activity in the brain. Inspired by findings in immune and epithelial cells, we discuss the underlying mechanisms and the implications for experience-dependent transcriptional regulation in health and disease. We conclude by presenting a holistic view of chromatin as potential molecular substrate for the integration and assimilation of environmental information that may constitute a conceptual basis for future research.ISSN:2158-318

Epigenetic Inheritance: Impact for Biology and Society—recent progress, current questions and future challenges

Epigenetic inheritance has emerged as a new research discipline that aims to study the mechanisms underlying the transmission of acquired traits across generations. Such transmission is well established in plants and invertebrates but remains not well characterized and understood in mammals. Important questions are how life experiences and environmental factors induce phenotypic changes that are passed to the offspring of exposed individuals, sometimes across several successive generations, what is the contribution of germ cells and what are the consequences for health and disease. These questions were recently discussed at the symposium Epigenetic Inheritance: Impact for Biology and Society organized every 2 years in Zürich, Switzerland. This review provides a summary of the research presented during the symposium and discusses current important questions, perspectives and challenges for the field in the future. Keywords: epigenetic inheritance; epigenetics; meeting report; transgenerational inheritanc

The epigenome under pressure: On regulatory adaptation to chronic stress in the brain

Chronic stress (CS) can have long-lasting consequences on behavior and cognition, that are associated with stable changes in gene expression in the brain. Recent work has examined the role of the epigenome in the effects of CS on the brain. This review summarizes experimental evidence in rodents showing that CS can alter the epigenome and the expression of epigenetic modifiers in brain cells, and critically assesses their functional effect on genome function. It discusses the influence of the developmental time of stress exposure on the type of epigenetic changes, and proposes new lines of research that can help clarify these changes and their causal involvement in the impact of CS.ISSN:0959-4388ISSN:1873-688

Long-Term Impact of Social Isolation and Molecular Underpinnings

Prolonged periods of social isolation can have detrimental effects on the physiology and behavior of exposed individuals in humans and animal models. This involves complex molecular mechanisms across tissues in the body which remain partly identified. This review discusses the biology of social isolation and describes the acute and lasting effects of prolonged periods of social isolation with a focus on the molecular events leading to behavioral alterations. We highlight the role of epigenetic mechanisms and non-coding RNA in the control of gene expression as a response to social isolation, and the consequences for behavior. Considering the use of strict quarantine during epidemics, like currently with COVID-19, we provide a cautionary tale on the indiscriminate implementation of such form of social isolation and its potential damaging and lasting effects in mental health.ISSN:1664-802

Enhancer RNAs: Insights Into Their Biological Role

Enhancers play a central role in the transcriptional regulation of metazoans. Almost a decade ago, the discovery of their pervasive transcription into noncoding RNAs, termed enhancer RNAs (eRNAs), opened a whole new field of study. The presence of eRNAs correlates with enhancer activity; however, whether they act as functional molecules remains controversial. Here we review direct experimental evidence supporting a functional role of eRNAs in transcription and provide a general pipeline that could help in the design of experimental approaches to investigate the function of eRNAs. We propose that induction of transcriptional activity at enhancers promotes an increase in its activity by an RNA-mediated titration of regulatory proteins that can impact different processes like chromatin accessibility or chromatin looping. In a few cases, transcripts originating from enhancers have acquired specific molecular functions to regulate gene expression. We speculate that these transcripts are either nonannotated long noncoding RNAs (lncRNAs) or are evolving toward functional lncRNAs. Further work will be needed to comprehend better the biological activity of these transcripts

Dynamics of transcriptional programs and chromatin accessibility in mouse spermatogonial cells from early postnatal to adult life

In mammals, spermatogonial cells (SCs) are undifferentiated male germ cells in testis quiescent until birth that self-renew and differentiate to produce spermatogenic cells and functional sperm across life. The transcriptome of SCs is highly dynamic and timely regulated during postnatal development. We examined if such dynamics involves changes in chromatin organization by profiling the transcriptome and chromatin accessibility in SCs from early postnatal stages to adulthood in mice using RNA-seq and ATAC-seq. By integrating transcriptomic and epigenomic features, we show that SCs undergo massive chromatin remodeling during postnatal development that correlates with distinct gene expression profiles and transcription factors (TF) motif enrichment. We identify genomic regions with significantly different chromatin accessibility in adult SCs that are marked by histone modifications associated with enhancers and promoters. Some of the regions with increased accessibility correspond to transposable element subtypes enriched in multiple TFs motifs and close to differentially expressed genes. Our results underscore the dynamics of chromatin organization in developing germ cells and the involvement of the regulatory genome.ISSN:2050-084

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Abstract 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