Angela Relógio

Charité Universitätsmedizin Berlin | Charité · Institute for Theoretical Biology, ITB, CC4

Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted...

Introduction Circadian rhythms (CRs) orchestrate intrinsic 24-hour oscillations which synchronize an organism’s physiology and behaviour with respect to daily cycles. CR disruptions have been linked to Parkinson’s Disease (PD), the second most prevalent neurodegenerative disorder globally, and are associated to several PD-symptoms such as sleep dis...

We investigated the diurnal rhythmicity of gene expression in microglia, the resident macrophages of the brain, in health and disease. Using RNA sequencing and single-cell analysis by RNAscope, we examined wild-type mice and the R6/2 transgenic mouse model of Huntington's disease (HD). Our findings suggest context-dependent rhythmic gene expression...

Glioblastoma is one of the most lethal cancers with current therapeutic options lacking major successes. This underlines the necessity to understand glioblastoma biology on other levels and use these learnings for the development of new therapeutic concepts. Mounting evidence in the field of circadian medicine points to a tight interplay between di...

Introduction Circadian rhythms (CR) regulate daily cycles in behavior, physiology and molecular processes. CRs are endogenous and vary across individuals. Seasonal changes can influence CR. Accordingly, rhythms with different characteristics (amplitude, phase) are depicted during the summer months, as compared to winter. Increasing evidence points...

Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression. Methods Here, we evaluated the role o...

Background Gliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from 2021 in 4 grades depending on molecular and histopathological criteria. Despite novel multimodal therapeutic approaches, the vast majority of gliomas (WHO grade III and IV)...

Increasing evidence points to a role of the circadian clock in the regulation of cancer hallmarks with a strong impact on the understanding and treatment of this disease. Anti-cancer treatment can be personalized considering treatment timing. Here we present a new mathematical model based on data from three colorectal cancer cell lines and core-clo...

Circadian medicine, the study of the effects of time on health and disease has seen an uprising in recent years as a means to enhance health and performance, and optimize treatment timing. Our endogenous time generating system -the circadian clock- regulates behavioural, physiological and cellular processes. Disruptions of the clock, via external f...

The circadian clock regulates cellular and molecular processes in mammals across all tissues including skeletal muscle, one of the largest organs in the human body. Dysregulated circadian rhythms are characteristic of aging and crewed spaceflight, associated with, for example, musculoskeletal atrophy. Molecular insights into spaceflight-related alt...

Background In many organisms, including humans, the timing of cellular processes is regulated by the circadian clock. At the molecular level the core-clock consists of transcriptional-translational-feedback loops including several genes such as BMAL1, CLOCK, PERs and CRYs generating circa 24-h rhythms in the expression of about 40% of our genes acr...

The circadian clock generates 24 h rhythms in behavioural, cellular and molecular processes. Malfunctions of the clock are associated with enhanced susceptibility to cancer, worse treatment response and poor prognosis. Clock-controlled genes are involved in cellular processes associated with tumour development and progression including metabolism o...

The circadian clock coordinates the timing of several cellular processes including transcription, the cell cycle, and metabolism. Disruptions in the clock machinery trigger the abnormal regulation of cancer hallmarks, impair cellular homeostasis, and stimulate tumourigenesis. Here we investigated the role of a disrupted clock by knocking out or kno...

Emerging evidence points towards a regulatory role of the circadian clock in alternative splicing (AS). Whether alterations in core-clock components may contribute to differential AS events is largely unknown. To address this, we carried out a computational analysis on recently generated time-series RNA-seq datasets from three core-clock knockout (...

A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a w...

Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colore...

Introduction/Background* Ovarian cancer (OC) is associated with the highest mortality rates among gynecological malignancies, with most patients being diagnosed in advanced stages. The most common histological subtype is high grade serous OC, which is characterized by deficiency in homologous recombination. Debulking surgery, followed by platinum b...

Scheduling anticancer drug administration over 24h may critically impact treatment success in a patient-specific manner. Here, we address personalization of treatment timing using a novel mathematical model of irinotecan cellular pharmacokinetics and –dynamics linked to a representation of the core clock and predicted treatment toxicity in a colore...

Background Obstructive Sleep Apnea (OSA) is a highly prevalent and underdiagnosed sleep disorder. Recent studies suggest that OSA might disrupt the biological clock, potentially causing or worsening OSA-associated comorbidities. However, the effect of OSA treatment on clock disruption is not fully understood. Methods The impact of OSA and short- (...

Objectives In this study, we investigated daily fluctuations in molecular (gene expression) and physiological (biomechanical muscle properties) features in human peripheral cells and their correlation with exercise performance. Methods 21 healthy participants (13 men and 8 women) took part in three test series: for the molecular analysis, 15 parti...

Tailoring medical interventions to a particular patient and pathology has been termed personalized medicine. The outcome of cancer treatments is improved when the intervention is timed in accordance with the patient’s internal time. Yet, one challenge of personalized medicine is how to consider the biological time of the patient. Prerequisite for t...

Impairment of circadian rhythms impacts carcinogenesis. SMAD4, a clock-controlled gene and central component of the TGFβ canonical pathway, is frequently mutated in pancreatic ductal adenocarcinoma (PDA), leading to decreased survival. Here, we used an in vitro PDA model of SMAD4-positive and SMAD4-negative cells to investigate the interplay betwee...

Abstract. Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an. important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to...

Accumulating evidence points to a link between circadian clock dysfunction and the molecular events that drive tumorigenesis. Here, we investigated the connection between the circadian clock and the hallmarks of cancer in an in vitro model of colorectal cancer (CRC). We used a cross-platform data normalization method to concatenate and compare avai...

Malfunctions of circadian clock trigger abnormal cellular processes and influence tumorigenesis. Using an in vitro and in vivo xenograft model, we show that circadian clock disruption via the downregulation of the core-clock genes BMAL1, PER2, and NR1D1 impacts the circadian phenotype of MYC, WEE1, and TP53, and affects proliferation, apoptosis, an...

Opportunistic modification of the tumour microenvironment by cancer cells enhances tumour expansion and consequently eliminates tumour suppressor components. We studied the effect of fibroblasts on the circadian rhythm of growth and protein expression in colon cancer HCT116 cells and found diminished oscillation in the proliferation of HCT116 cells...

Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenanc...

The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in kee...

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomi...

Mounting evidence points to a role of the circadian clock in the temporal regulation of post-transcriptional processes in mammals, including alternative splicing (AS). In this study, we carried out a computational analysis of circadian and ultradian rhythms on the transcriptome level to characterise the landscape of rhythmic AS events in published...

The circadian clock regulates key cellular processes and its dysregulation is associated to several pathologies including cancer. Although the transcriptional regulation of gene expression by the clock machinery is well described, the role of the clock in the regulation of post-transcriptional processes, including splicing, remains poorly understoo...

Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant...

In mammals, most molecular and cellular processes show circadian changes, leading to daily variations in physiology and ultimately in behaviour. Such daily variations induce a temporal coordination of processes that is essential to ensure homeostasis and health. Thus, it is of no surprise that pharmacokinetics (PK) and pharmacodynamics (PD) of many...

The circadian clock is an endogenous time-generating system accountable for the synchrony between the internal and the geophysical time. In recent years, chronobiology research has demonstrated that the circadian regulation of numerous molecular and cellular processes leads to a temporal control of physiology and behaviour. These findings alert to...

Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present w...

In living organisms, biological clocks regulate 24 h (circadian) molecular, physiological, and behavioral rhythms to maintain homeostasis and synchrony with predictable environmental changes, in particular with those induced by Earth’s rotation on its axis. Harmonics of these circadian rhythms having periods of 8 and 12 h (ultradian) have been docu...

Raw data obtained from PhylomeDB, NCBI HomoloGene, and Phyletic age.

Dataset for gene evolutionary properties.

Most statistically significant pathways in gene expression analysis in mouse liver.

Top five enriched pathways for the three oscillating gene subsets.

Comparative analysis based on −log(p-value) of enriched pathways among the three oscillating gene subsets.

Original output of CodonW.

Command lines and raw output.

Raw outputs of CodonW and JCat tools.

Summary of the top ranking over-represented Transcription Factor Binding Sites, as estimated by AME (MEME suite) comparative analyses.

Day length estimation through ages.

A bidirectional interaction between the circadian network and effector mechanisms of immunity brings on a proper working of both systems. In the present study, we used Hodgkin lymphoma (HL) as an experimental model for a type of cancer involving cells of the immune system. We identified this cancer type among haematological malignancies has having...

KD efficiency after shRNA-mediated kD of BMAL1 and HKDC1. Gene expression analysis of BMAL1 in SW480 (a) and SW620 (b) cells and HKDC1 in SW480 (c) and SW620 (d) cells after shRNA-mediated BMAL1-KD and HKDC1-KD. Gene expression is shown compared to the corresponding control gene. Mean ± SEM, n = 3. KD efficiency in SW480-shBMAL1 cells: 0.317 ± 0.00...

Metabolic activity of SW480 and SW620 control and shBMAL1 cells after oxaliplatin treatment. (a) Glycolysis of SW480 (left panel) and SW620 (right panel) control and shBMAL1 cells at three different timepoints after synchronization (18 h, 21 h, 24 h). Cells were either untreated or treated with oxaliplatin. Mean ± SEM, n = 5. (b) Glycolytic capacit...

Proliferation curve analysis. Statistical analysis was done for every timepoint of the proliferation curve to test for significant differences between the different conditions.

Changes in the core-clock of SW480 and SW620 cells lead to changes in metabolic pathways. (a) Phase-ordered, median-normalized heatmap of core-clock genes in SW480 and SW620 cells. Phase-ordering was performed based on SW480 expression data and the same ordering of genes was used for SW620 cells. (b) Phase-ordered, median-normalized heatmap of gene...

BMAL1 promoter activity in SW480 and SW620 cells and time-dependent gene expression after BMAL1-KD. (a) SW480 and (b) SW620 cells were lentivirally transduced either with an empty-vector (control) or with an shBMAL1-construct. Additionally, cells were lentivirally transduced with a Bmal1-promoter driven luciferase construct. Bioluminescence was mea...

Determination of treatment concentration for WZB117 treatment. To determine the appropriate treatment concentration with WZB117, SW480-ctrl, SW480-shBMAL1, SW620-ctrl and SW620-shBMAL1 cells were treated with different concentrations of WZB117 and the cytotoxicity was determined. Based on the calculated IC50 value, the concentration of treatment wa...

Metabolic network analysis. Expression data gained from a 24 h microarray analysis of SW480 and SW620 cells was mapped to a reconstruction of human metabolism.

The circadian clock in human fallopian tube organoids. (a) Bioluminescence measurements of human fallopian tube organoids transduced with a BMAL1-promoter driven luciferase construct. Bioluminescence was measured for 14 consecutive days. Shown is one representative replicate. 24 h time-course RT-qPCR measurements of BMAL1 (b) and HKDC1 (c) in human...

Viability, cytotoxicity and apoptosis in SW480 and SW620 cells. (a) Viability, (b) cytotoxicity and (c) apoptosis in SW480 (upper panel) and SW620 (lower panel) control and shBMAL1 cells synchronized at different timepoints. Cells were either untreated or treated with WZB117 or oxaliplatin. Mean ± SEM, n = 3. Significant changes (p < .05) between d...

Statistical analysis of circadian parameters of genes and proteins. Circadian parameters (p-value for oscillatory behavior, acrophase, amplitude, mesor) for clock and clock-regulated genes and proteins in SW480 and SW620 cells determined using RAIN and harmonic regression analysis.

Over-representation analysis. An over-representation analysis was performed with three sets of genes: genes oscillating in SW480 and SW620 cells, genes oscillating in SW480 cells only and genes oscillating in SW620 cells only.

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment respo...

Functional annotation of SW480 circadian transcript clusters reveals splicing processes among enriched GO and KEGG terms. (a) The circadian transcripts of SW480 were grouped in four clusters. Each colored line represents the RMA-preprocessed expression level of a transcript transformed to the standard normal distribution. The colors of the gene exp...

Differentially rhythmic expression patterns of splicing-related genes in CRC progression. Circadian transcriptional expression patterns in SW480 (blue line) and SW620 cells (green line) of all spliceosome components and SFs that showed 24-h oscillations in at least one of the cell lines. The adjusted p-value denotes the results of the DODR analysis...

Enriched GO terms (biological processes) for the candidate genes with differential AS events.

Functional annotation of SW620 circadian transcript clusters reveals splicing processes among enriched GO and KEGG terms. (a) The circadian transcripts of SW620 were grouped in four clusters. Each colored line represents the RMA-preprocessed expression level of a transcript transformed to the standard normal distribution. The colors of the gene exp...

Temporal exon expression patterns of selected exons with circadian AS events. Exon expression profiles for selected exons with circadian AS events in either SW480 (blue) and/or SW620 cells (green).

Alterations of the circadian clock in CRC primary tumors and metastasis. (a) Heatmaps of Spearman correlation (rho) between each pair of core-clock genes in a set of 34 CRC cell lines (GSE97023) in comparison to a mammalian reference set (GSE54650). (b) Box-plot of the log-likelihoods of the ZeitZeiger predictions of CT for SW480 (blue) and SW620 (...

Phase-clustered pathways whose associated genes showed significant shifts in their peak expression in the CRC progression model.

Single-cell time-course measurements of REV-ERBα protein abundance in CRC cell lines. The fluorescence intensity of a REV-ERBα-VNP fusion protein was measured for 38 h in single live-cells from SW480 (a) and SW620 (b) (n = 4).