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RNA sequencing of livers from Per2-/- and WT mice following MC38 cancer cells injection reveals transcriptional differences as early as 7 days post injection

ABSTRACT: The circadian clock regulates diverse physiological processes by maintaining a 24-hour gene expression pattern. Genetic and environmental cues that disrupt normal clock rhythms can lead to cancer, yet the extent to which this effect is controlled by the cancer cells versus non-malignant cells in the tumor microenvironment (TME) is not clear. Here we set out to address this question, by selective manipulation of circadian clock genes in the TME. In two different mouse models of cancer we find that expression of the core clock gene Per2 in the TME is crucial for tumor initiation and metastatic colonization, whereas another core gene, Per1, is dispensable. We further show that loss of Per2 in the TME leads to significant transcriptional changes in response to cancer cell introduction. These changes may contribute to a tumor-suppressive microenvironment. Thus, our work unravels an unexpected protumorigenic role for the core clock gene Per2 in the TME, with potential implications for therapeutic dosing strategies and treatment regimens.

ORGANISM(S): Mus musculus

PROVIDER: GSE156450 | GEO | 2020/10/15

REPOSITORIES: GEO

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Negative reciprocal regulation between SIRT1 and Per2 in circadian clock during aging (ChIP-Seq)

Project description:SIRT1 is involved in both aging and circadian clock regulation, yet the link between the two processes in relation to SIRT1 function is unclear. Analyzing SIRT1-deficient cells and mice, we demonstrated that SIRT1 and Per2 constitute a reciprocal negative regulation loop that plays important roles in modulating circadian rhythmicity, metabolism and aging. SIRT1-deficient mice exhibit profound premature aging and enhanced H4K16 acetylation in the promoter of Per2 leading to its overexpression; in turn, Per2 suppresses SIRT1 transcription through binding to SIRT1 promoter at the CLOCK/BMAL1 site. We further demonstrated that absence of SIRT1 or ectopic overexpression of Per2 in the liver resulted in an accelerated pace of circadian rhythm and dysregulated amplitude, mimicking the natural process of circadian shortening in aged mice. Thus the interplay between SIRT1 and Per2 provides a link between the life-long sequence of aging and circadian clock maintenance.

2016-08-08 | GSE54449 | GEO

Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging (microarray expression)

Project description:Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.

2016-08-08 | GSE54436 | GEO

Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging (microarray expression)

2016-08-08 | E-GEOD-54436 | biostudies-arrayexpress

PER2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

Project description:Implantation is dependent on synchronized interactions between the conceptus and surrounding decidual cells but the involvement of clock genes in this process is not well understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK and BMAL1 and repressors encoded by PER and CRY genes. Here we show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Downregulation was preceded by reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter and occurred between 12 - 24 h after exposure to a deciduogenic stimulus. RNA sequencing revealed that premature inhibition of PER2 by siRNA knockdown leads to a grossly disorganised decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators amongst the 1,121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of mid-luteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure. Thus, PER2 synchronizes mitotic expansion of HESCs with a periodic decidual gene expression; uncoupling of these events may cause persistent pregnancy failure. Endometrial mRNA profiles of paired control (siRNA-NT) and siRNA-PER2 were generated by deep sequencing, in triplicate using Illumina

2015-09-16 | E-GEOD-62854 | biostudies-arrayexpress

Nutrient Abundance Signals the Changing of the Seasons by Phosphorylating PER2

Project description:The circadian clock synchronizes metabolic and behavioral cycles with the rotation of the Earth by integrating environmental cues, such as light. Nutrient content also regulates the clock, though how and why this environmental signal affects the clock remains incompletely understood. Here, we elucidate a role for nutrient in regulating circadian alignment to seasonal photoperiods. High fat diet (HFD) promoted entrainment to a summer light cycle and inhibited entrainment to a winter light cycle by phosphorylating PER2 on serine 662. PER2-S662 phospho-mimetic mutant mice were incapable of entraining to a winter photoperiod, while PER2-S662 phospho-null mutant mice were incapable of entraining to a summer photoperiod, even in the presence of HFD. Multi-omic experimentation in conjunction with isocaloric hydrogenated-fat feeding, revealed a role for polyunsaturated fatty acids in nutrient-dependent seasonal entrainment. Altogether, we identify the mechanism whereby nutrient content shifts circadian rhythms to anticipate seasonal photoperiods in which that nutrient state predominates.

2024-01-29 | GSE254155 | GEO

PER2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

2015-09-16 | GSE62854 | GEO

Per2 regulation of mammary gland development and branching morphogenesis via cell fate determination

Project description:Circadian rhythms play key roles in daily physiological functions, development, and cancer. Period 2 (PER2) is a repressive element which inhibits transcription activated by positive clock elements resulting in diurnal cycling of genes. Here we show, that outside of time keeping, PER2 has a non-circadian function that is critical to mammary gland development. Virgin Per2 deficient mice, Per2ldc, have underdeveloped glands containing fewer bifurcations and terminal ducts. Using a transplantation model, we show that these changes are intrinsic to the gland and furthermore identify changes in cell fate commitment. Per2ldc mouse mammary glands have a luminal/basal bi-potent phenotype in cells of the ductal epithelium. We identified co-localization of E-cadherin and Keratin 14 in luminal cells and decreased p63 staining and gene expression in myoepithelial cells. Moreover, Per2ldc mice overexpress SLUG, which is related to mammary stem cell maintenance and EMT. Similar results were demonstrated using MCF10A and shPER2 MCF10A cell lines. Collectively this study reveals a critical non-circadian function of PER2 in mammary gland development, validates the Per2ldc model, and describes a potential role for PER2 in breast cancer.

2018-01-24 | GSE109522 | GEO

More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα

Project description:Circadian rhythms, governed by the dominant central as well as various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion, and metabolism. In certain contexts, regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period 2 (Per2) and RAR-related orphan receptor alpha (RORα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem involved in the homeostasis of amine groups. Very divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the Per2, and non-oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity, and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determine a finely tuned adaptation of muscle tissue to perturbations in health and disease.

2024-01-02 | GSE243522 | GEO

Transcriptome Sequencing Analysis (RNA-Seq) of Bone Marrow Hematopoietic Stem Cells from Per2-mutant Mice

Project description:Circadian rhythm (CR) and environmental low-dose radiation (LDR) evident on Earth’s surface may have coordinated in the evolution of early life; disturbed CR and/or overexposure to radiation are linked with aging and many human diseases including cancer. Although CR affects tumor response and normal tissue radiosensitivity in cancer radiotherapy, it is unclear how CR proteins function in LDR induced radioprotection. Herein, we demonstrated that mice carrying a deficient Period2 gene (C57BL-Per2 def ), a core CR regulator, were highly sensitive to radiation. Compared to Per2 wt mice, the population of bone marrow hemopoietic stem cells (BMHSCs) was reduced and a cluster of genes responsible for DNA damage repair and mitochondrial metabolism was silenced in the Per2 def BMHSCs . Consistently, unlike Per2 wt human and mouse cells capable of inducible radioresistance by LDR, Per2 def cells failed to induce such adaptive protection. Furthermore, LDR enhanced PER2 protein level together with phosphorylated GSK3β (pGSK3β) in the Wnt/β-catenin signaling pathway. Interaction of PER2 with pGSK3β activated β -catenin that in turn transactivated Per2 and other prosurvival genes. These results provide new insights into how CR and LDR communicate in genotoxic stress response. The PER2/pGSK3β/β-catenin/Per2 pathway may serve as a therapeutic approach to reduce normal cell injury in cancer radiotherapy.

2022-11-04 | GSE184407 | GEO

Core Circadian Clock Genes Per1 and Per2 regulate the Rhythm in Photoreceptor Outer Segment Phagocytosis [RPE]

Project description:Retinal photoreceptors undergo daily renewal of their distal outer segments, a process indispensable for maintaining retinal health. Photoreceptor Outer Segment (POS) phagocytosis occurs as a daily peak, roughly about one hour after light onset. However, the underlying cellular and molecular mechanisms which initiate this process are still unknown. Here we show that, under constant darkness, mice deficient for core circadian clock genes (Per1 and Per2), lack a daily peak in POS phagocytosis. By qPCR analysis we found that core clock genes were rhythmic over 24h in both WT and Per1, Per2 double mutant whole retinas. More precise transcriptomics analysis of laser capture microdissected WT photoreceptors revealed no differentially expressed genes between time-points preceding and during the peak of POS phagocytosis. By contrast, we found that microdissected WT retinal pigment epithelium (RPE) had a number of genes that were differentially expressed at the peak phagocytic time-point compared to adjacent ones. We also found a number of differentially expressed genes in Per1, Per2 double mutant RPE compared to WT ones at the peak phagocytic time-point. Finally, based on STRING analysis we found a group of interacting genes which potentially drive POS phagocytosis in the RPE. This potential pathway consists of genes such as: Pacsin1, Syp, Camk2b and Camk2d among others. Our findings indicate that Per1 and Per2 are necessary clock components for driving POS phagocytosis and suggest that this process is transcriptionally driven by the RPE.

2021-06-01 | GSE172438 | GEO

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