A signaling pathway for transcriptional regulation of sleep amount in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182907 | GEO | 2022/09/18
REPOSITORIES: GEO
Similar Datasets
Project description:Different mammalian species vary greatly in their daily sleep quota, ranging from 2-4 hours in giraffes to 20-22 hours in koalas and bats. In humans, the sleep quantity and quality of individuals are governed by genetic factors and exhibit age-dependent variations. However, the molecular pathways and effector mechanisms that regulate daily sleep need in mammals remain unknown. Here, using an adult brain chimeric (ABC)-expression/knockout (KO) system for somatic genetics analysis of sleep in adult mice, we report that gain-of-function of histone deacetylases HDAC4/5 significantly reduces, whereas loss-of-function of HDAC4/5 increases daily non-rapid eye movement sleep (NREMS) amount and delta power–two key indicators of sleep need. Similarly, ABC-expression of cAMP-response element binding protein (CREB) or A-CREB, an inhibitor of transcriptional activity of CREB, decreases or increases NREMS amount and delta power, respectively. A combination of genetic and transcriptomic analysis reveals that HDAC4 functions in tandem with CREB in both transcriptional and sleep regulation. Consistent with their functions downstream of LKB1-SIK3 kinase cascade, ABC-expression of HDAC4/5CA or CREB rescues hypersomnia of Sik3E13∆/+ mice, whereas ABC-expression of SIK3/SLP-ST221E or HDAC(4+5)VP16 rescues insomnia of ABC-Lkb1KO mice. Taken together, these results identify LKB1-SIK3-HDAC4/5-CREB as the first major molecular pathway for transcriptional regulation of daily sleep need in mammals.
2022-09-19 | GSE182805 | GEO
Project description:In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression. Circadian behavior and sleep were normal at baseline. The response to SD of 2 electrophysiological markers of sleep homeostasis, electroencephalography (EEG) θ power during wakefulness and δ power during sleep, were greater in the Per35/5 mice. During recovery, the Per35/5 mice fully compensated for the SD-induced deficit in δ power, but the Per34/4 and wild-type mice did not. Sleep homeostasis-related transcripts (e.g., Homer1, Ptgs2, and Kcna2) were differentially expressed between the humanized mice, but circadian clock genes were not. These data are in accordance with the hypothesis derived from human data that the PER3 VNTR polymorphism modifies the sleep homeostatic response without significantly influencing circadian parameters.-Hasan, S., van der Veen, D. R., Winsky-Sommerer, R., Hogben, A., Laing, E. E., Koentgen, F., Dijk, D.-J., Archer, S. N. A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.
2014-03-11 | GSE55495 | GEO
Project description:In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression. Circadian behavior and sleep were normal at baseline. The response to SD of 2 electrophysiological markers of sleep homeostasis, electroencephalography (EEG) θ power during wakefulness and δ power during sleep, were greater in the Per35/5 mice. During recovery, the Per35/5 mice fully compensated for the SD-induced deficit in δ power, but the Per34/4 and wild-type mice did not. Sleep homeostasis-related transcripts (e.g., Homer1, Ptgs2, and Kcna2) were differentially expressed between the humanized mice, but circadian clock genes were not. These data are in accordance with the hypothesis derived from human data that the PER3 VNTR polymorphism modifies the sleep homeostatic response without significantly influencing circadian parameters.-Hasan, S., van der Veen, D. R., Winsky-Sommerer, R., Hogben, A., Laing, E. E., Koentgen, F., Dijk, D.-J., Archer, S. N. A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.
2014-03-11 | GSE55494 | GEO
Project description:Osteoarthritis is a common joint disorder that causes debilitating conditions among the elderly. Risk factors of osteoarthritis include age, which is often associated with the thinning of articular cartilage. We generated conditional knockout mice that lack salt-inducible kinase 3 (Sik3) specifically in chondrocytes after birth by tamoxifen administration. Deletion of Sik3 at 2 or 8 weeks after birth increased the thickness of articular cartilage by increasing the chondrocyte population. Additionally, Sik3 deletion protected cartilage against osteoarthritis development. We identified the edible Pteridium aquilinum ingredient, pterosin B, as a compound that inhibits the Sik3 pathway. Intraarticular injection of pterosin B protected cartilage against osteoarthritis development. Sik3 deletion or pterosin B treatment inhibited activation of the hypertrophic program through the histone deacetylase 4 (Hdac4) pathway, increased Prg4 expression in chondrocytes, and protected cartilage against osteoarthritic attack. Collectively, our results suggest Sik3 is a regulator that regulates homeostasis of articular cartilage thickness and a target for treatment of osteoarthritis, and that pterosin B can be the lead compound for relevant drugs.
2016-03-21 | GSE75995 | GEO
Project description:Two types of UCP1 positive cells-brown and beige adipocytes exist in mammals. Beige adipocytes are very plastic, and can be dynamically regulated by environment.Beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue (iWAT) lost thermogenic gene expression and multilocular morphology at adult stage, but cold could restore their “beigeing” characteristics, a phenomenon termed as beige adipocyte renaissance. Our results showed that beige cell maintenance and renaissance in adult mice were regulated by cAMP and HDAC4 signaling in white adipocytes non-cell autonomously. Genetic modulations of various components of this cAMP-HDAC4 cascade (e.g. LKB1) led to persistent browning and reduced adiposity independent of thermogenesis. To further study the mechanisms of beige adipocytes maintenance, we performed RNA-seq with samples from inguinal white adipose tissues of WT, AdipoqCre LKB1 F/F, and AdipoqCre LKB1 F/F; HDAC4 F/F mice.Our studies will move the beige adipocyte field forward and attract clinical applications to target beige adipocyte renaissance.
2018-02-14 | GSE85335 | GEO
Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Despite being implicated in the regulation of a variety of cellular processes, the mechanisms by which LKB1 constrains lung tumor growth and progression remains an area of intense investigation. Purpose: To assess the impact of CRISPR/Cas9-mediated targeting of the canonical substrates of Lkb1 on tumor size within the context of a genetically engineered mouse model of oncogenic Kras-driven lung adenocarcinoma. Approach: Comparisons of tumor size across genetic perturbations were conducting by measuring tumor sizes via tumor barcode sequencing (Rogers, et al. 2017 Nature Methods). Briefly, tumors were initiated in KrasLSL-G12D/+;R26LSL-Tomato, KrasLSL-G12D/+;Lkb1flox/flox;R26LSL-Tomato;H11LSL-Cas9, and KrasLSL-G12D/+;R26LSL-Tomato;H11LSL-Cas9 mice using a pool of Lenti-sgRNA/Cre vectors that encode a cassette comprised of an sgRNA-specific ID along with clonal identifier. Following, tumor development/progression, the two-component lentiviral cassettes integrated within transduced populations were amplified from genomic DNA extracted from whole lungs homogenates and subjected to next-generation sequencing. From the resulting reads, barcode pileups were generated and filtered prior to translation to absolute numbers of cancer cells via normalization to spiked-in samples of known quantities of cancer cells. The resultant tumor size distribution were then analyzed by multiple statistical measures as described by Rogers, et al. Results: Lkb1 targeting dramatically increased tumor size in the Kras-only setting relative to functionally inert sgRNAs. Unlike other families of Lkb1 substrates, the targeting of the salt inducible kinase (Sik) family increased tumor growth comparable to Lkb1 targeting. In contrast to targeting the paralogs Sik1 and Sik3 individually, dual targeting of Sik1 and Sik3 enhanced tumor growth. Sik targeting in the Lkb1-deficient setting also modestly increased tumor size whereas Lkb1 targeting had no effect. Conclusions: Siks are potent tumor suppressors belonging the family of canonical Lkb1 substrates. Siks retain some tumor-suppressive activity in the absence of Lkb1.
2019-07-03 | GSE133698 | GEO
Project description:STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation. Elucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) tumor suppressor appears to be inactivated in human cancer, however, somatic missense mutations also occur. Despite of our increased knowledge about LKB1 function, the role/s of these alterations in cancer are mostly unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three, out of the four mutants, lost their tumor suppressor capabilities and showed a deficient kinase activity. The remaining mutant conserved the enzymatic activity, but conferred an increased cell motility. Mechanistically, LKB1 mutants promoted the differential gene expression regulation of vesicle trafficking regulating molecules, adhesion molecules and cytokines, that correlated with the identified protein networks associated to the comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one of them induced inflammation and hemorrhagic tumors that correlated with the deregulated levels of cytokines. Altogether, our findings uncover oncogenic roles of LKB1 somatic mutations helping to understand their contribution to cancer.
2021-09-09 | PXD018041 | Pride
Project description:This a model from the article:
Sleep deprivation in a quantitative physiologically based model of the ascending
arousal system.
Phillips AJ, Robinson PA. J Theor Biol
2008 Dec 21;255(4):413-23 18805427
,
Abstract:
A physiologically based quantitative model of the human ascending arousal system
is used to study sleep deprivation after being calibrated on a small set of
experimentally based criteria. The model includes the sleep-wake switch of
mutual inhibition between nuclei which use monoaminergic neuromodulators, and
the ventrolateral preoptic area. The system is driven by the circadian rhythm
and sleep homeostasis. We use a small number of experimentally derived criteria
to calibrate the model for sleep deprivation, then investigate model predictions
for other experiments, demonstrating the scope of application. Calibration gives
an improved parameter set, in which the form of the homeostatic drive is better
constrained, and its weighting relative to the circadian drive is increased.
Within the newly constrained parameter ranges, the model predicts repayment of
sleep debt consistent with experiment in both quantity and distribution,
asymptoting to a maximum repayment for very long deprivations. Recovery is found
to depend on circadian phase, and the model predicts that it is most efficient
to recover during normal sleeping phases of the circadian cycle, in terms of the
amount of recovery sleep required. The form of the homeostatic drive suggests
that periods of wake during recovery from sleep deprivation are phases of
relative recovery, in the sense that the homeostatic drive continues to converge
toward baseline levels. This undermines the concept of sleep debt, and is in
agreement with experimentally restricted recovery protocols. Finally, we compare
our model to the two-process model, and demonstrate the power of physiologically
based modeling by correctly predicting sleep latency times following deprivation
from experimental data.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Phillips AJ, Robinson PA. (2008) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230110 | BioModels
Project description:This a model from the article:
Sleep deprivation in a quantitative physiologically based model of the ascending
arousal system.
Phillips AJ, Robinson PA. J Theor Biol
2008 Dec 21;255(4):413-23 18805427
,
Abstract:
A physiologically based quantitative model of the human ascending arousal system
is used to study sleep deprivation after being calibrated on a small set of
experimentally based criteria. The model includes the sleep-wake switch of
mutual inhibition between nuclei which use monoaminergic neuromodulators, and
the ventrolateral preoptic area. The system is driven by the circadian rhythm
and sleep homeostasis. We use a small number of experimentally derived criteria
to calibrate the model for sleep deprivation, then investigate model predictions
for other experiments, demonstrating the scope of application. Calibration gives
an improved parameter set, in which the form of the homeostatic drive is better
constrained, and its weighting relative to the circadian drive is increased.
Within the newly constrained parameter ranges, the model predicts repayment of
sleep debt consistent with experiment in both quantity and distribution,
asymptoting to a maximum repayment for very long deprivations. Recovery is found
to depend on circadian phase, and the model predicts that it is most efficient
to recover during normal sleeping phases of the circadian cycle, in terms of the
amount of recovery sleep required. The form of the homeostatic drive suggests
that periods of wake during recovery from sleep deprivation are phases of
relative recovery, in the sense that the homeostatic drive continues to converge
toward baseline levels. This undermines the concept of sleep debt, and is in
agreement with experimentally restricted recovery protocols. Finally, we compare
our model to the two-process model, and demonstrate the power of physiologically
based modeling by correctly predicting sleep latency times following deprivation
from experimental data.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Phillips AJ, Robinson PA. (2008) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230115 | BioModels
Project description:Background: Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T cell attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. Methods: To identify novel genes that protect tumor cells from effective T cell-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with TILs and antigen-specific T cells. Results: The screening revealed 108 potential genes that protected tumor cells from T cell attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibition of SIK3 in tumor cells dramatically increased T cell-mediated cytotoxicity in several in vitro co-culture models, using different sources of tumor and T cells. Consistently, adoptive T cell transfer of TILs led to tumor growth inhibition of SIK3 depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to TNF secreted by tumor-activated T cells. SIK3 promoted NF-ΚB nuclear translocation and inhibited Caspase-8 and -9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of pro-survival genes under the TNF-NF-ΚB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase (IKK) and NF-kappa-B inhibitor alpha (IκBα) on the one side, and to inhibition of histone deacetylase 4 (HDAC4) on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3 dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic T cell activity and poor prognosis.
2022-06-06 | GSE202304 | GEO