The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the , , and genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.
Andrews J. L., Zhang X., McCarthy J. J., McDearmon E. L., Hornberger T. A., Russell B., Campbell K. S., Arbogast S., Reid M. B., Walker J. R., Hogenesch J. B., Takahashi J. S., Esser K. A., CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function, 10.1073/pnas.1014523107
Chen Z., Yoo S.-H., Park Y.-S., Kim K.-H., Wei S., Buhr E., Ye Z.-Y., Pan H.-L., Takahashi J. S., Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening, 10.1073/pnas.1118034108
Cho Han, Zhao Xuan, Hatori Megumi, Yu Ruth T., Barish Grant D., Lam Michael T., Chong Ling-Wa, DiTacchio Luciano, Atkins Annette R., Glass Christopher K., Liddle Christopher, Auwerx Johan, Downes Michael, Panda Satchidananda, Evans Ronald M., Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β, 10.1038/nature11048
Creyghton M. P., Cheng A. W., Welstead G. G., Kooistra T., Carey B. W., Steine E. J., Hanna J., Lodato M. A., Frampton G. M., Sharp P. A., Boyer L. A., Young R. A., Jaenisch R., Histone H3K27ac separates active from poised enhancers and predicts developmental state, 10.1073/pnas.1016071107
Curtis Anne M., Fagundes Caio T., Yang Guangrui, Palsson-McDermott Eva M., Wochal Paulina, McGettrick Anne F., Foley Niamh H., Early James O., Chen Lihong, Zhang Hanrui, Xue Chenyi, Geiger Sarah S., Hokamp Karsten, Reilly Muredach P., Coogan Andrew N., Vigorito Elena, FitzGerald Garret A., O’Neill Luke A. J., Circadian control of innate immunity in macrophages by miR-155 targetingBmal1, 10.1073/pnas.1501327112
Damiola F., Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus, 10.1101/gad.183500
Duong Hao A, Weitz Charles J, Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes, 10.1038/nsmb.2746
Eckel-Mahan Kristin L., Patel Vishal R., de Mateo Sara, Orozco-Solis Ricardo, Ceglia Nicholas J., Sahar Saurabh, Dilag-Penilla Sherry A., Dyar Kenneth A., Baldi Pierre, Sassone-Corsi Paolo, Reprogramming of the Circadian Clock by Nutritional Challenge, 10.1016/j.cell.2013.11.034
Eichenfield Dawn Z, Troutman Ty Dale, Link Verena M, Lam Michael T, Cho Han, Gosselin David, Spann Nathanael J, Lesch Hanna P, Tao Jenhan, Muto Jun, Gallo Richard L, Evans Ronald M, Glass Christopher K, Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages, 10.7554/elife.13024
Fang Bin, Everett Logan J., Jager Jennifer, Briggs Erika, Armour Sean M., Feng Dan, Roy Ankur, Gerhart-Hines Zachary, Sun Zheng, Lazar Mitchell A., Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo, 10.1016/j.cell.2014.10.022
Fonjallaz P., Ossipow V., Wanner G., Schibler U., The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue-specific expression, but have different target promoter preferences., 10.1002/j.1460-2075.1996.tb00365.x
Arkan Melek C, Hevener Andrea L, Greten Florian R, Maeda Shin, Li Zhi-Wei, Long Jeffrey M, Wynshaw-Boris Anthony, Poli Giuseppe, Olefsky Jerrold, Karin Michael, IKK-β links inflammation to obesity-induced insulin resistance, 10.1038/nm1185
Fuda Nicholas J., Ardehali M. Behfar, Lis John T., Defining mechanisms that regulate RNA polymerase II transcription in vivo, 10.1038/nature08449
Gerber Alan, Esnault Cyril, Aubert Gregory, Treisman Richard, Pralong François, Schibler Ueli, Blood-Borne Circadian Signal Stimulates Daily Oscillations in Actin Dynamics and SRF Activity, 10.1016/j.cell.2012.12.027
Gibbs J. E., Blaikley J., Beesley S., Matthews L., Simpson K. D., Boyce S. H., Farrow S. N., Else K. J., Singh D., Ray D. W., Loudon A. S. I., The nuclear receptor REV-ERB mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines, 10.1073/pnas.1106750109
Hotamisligil G., Shargill N., Spiegelman B., Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, 10.1126/science.7678183
Hughes Michael E., DiTacchio Luciano, Hayes Kevin R., Vollmers Christopher, Pulivarthy S., Baggs Julie E., Panda Satchidananda, Hogenesch John B., Harmonics of Circadian Gene Transcription in Mammals, 10.1371/journal.pgen.1000442
Hughes Michael E., Hong Hee-Kyung, Chong Jason L., Indacochea Alejandra A., Lee Samuel S., Han Michael, Takahashi Joseph S., Hogenesch John B., Brain-Specific Rescue of Clock Reveals System-Driven Transcriptional Rhythms in Peripheral Tissue, 10.1371/journal.pgen.1002835
Im Seung-Soon, Yousef Leyla, Blaschitz Christoph, Liu Janet Z., Edwards Robert A., Young Stephen G., Raffatellu Manuela, Osborne Timothy F., Linking Lipid Metabolism to the Innate Immune Response in Macrophages through Sterol Regulatory Element Binding Protein-1a, 10.1016/j.cmet.2011.04.001
Kaikkonen Minna U., Spann Nathanael J., Heinz Sven, Romanoski Casey E., Allison Karmel A., Stender Joshua D., Chun Hyun B., Tough David F., Prinjha Rab K., Benner Christopher, Glass Christopher K., Remodeling of the Enhancer Landscape during Macrophage Activation Is Coupled to Enhancer Transcription, 10.1016/j.molcel.2013.07.010
Kim Jin Young, Kwak Pieter Bas, Weitz Charles J., Specificity in Circadian Clock Feedback from Targeted Reconstitution of the NuRD Corepressor, 10.1016/j.molcel.2014.10.017
Barish Grant D., Tangirala Rajenda K., Chromatin Immunoprecipitation, Methods in Molecular Biology (2013) ISBN:9781603273688 p.327-342, 10.1007/978-1-60327-369-5_15
Kohsaka Akira, Laposky Aaron D., Ramsey Kathryn Moynihan, Estrada Carmela, Joshu Corinne, Kobayashi Yumiko, Turek Fred W., Bass Joseph, High-Fat Diet Disrupts Behavioral and Molecular Circadian Rhythms in Mice, 10.1016/j.cmet.2007.09.006
Koike N., Yoo S.-H., Huang H.-C., Kumar V., Lee C., Kim T.-K., Takahashi J. S., Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals, 10.1126/science.1226339
Lam Michael T. Y., Cho Han, Lesch Hanna P., Gosselin David, Heinz Sven, Tanaka-Oishi Yumiko, Benner Christopher, Kaikkonen Minna U., Kim Aneeza S., Kosaka Mika, Lee Cindy Y., Watt Andy, Grossman Tamar R., Rosenfeld Michael G., Evans Ronald M., Glass Christopher K., Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription, 10.1038/nature12209
Langmead Ben, Trapnell Cole, Pop Mihai, Salzberg Steven L, Ultrafast and memory-efficient alignment of short DNA sequences to the human genome, 10.1186/gb-2009-10-3-r25
Li Zhi-Wei, Chu Wenming, Hu Yinling, Delhase Mireille, Deerinck Tom, Ellisman Mark, Johnson Randall, Karin Michael, The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis, 10.1084/jem.189.11.1839
Love Michael I, Huber Wolfgang, Anders Simon, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, 10.1186/s13059-014-0550-8
Marpegán Luciano, Bekinschtein Tristán A., Costas Monica A., Golombek Diego A., Circadian responses to endotoxin treatment in mice, 10.1016/j.jneuroim.2004.11.003
McLean Cory Y, Bristor Dave, Hiller Michael, Clarke Shoa L, Schaar Bruce T, Lowe Craig B, Wenger Aaron M, Bejerano Gill, GREAT improves functional interpretation of cis-regulatory regions, 10.1038/nbt.1630
Meffert Mollie K, Chang Jolene M, Wiltgen Brian J, Fanselow Michael S, Baltimore David, NF-κB functions in synaptic signaling and behavior, 10.1038/nn1110
Bass Joseph, Lazar Mitchell A., Circadian time signatures of fitness and disease, 10.1126/science.aah4965
Morf J., Rey G., Schneider K., Stratmann M., Fujita J., Naef F., Schibler U., Cold-Inducible RNA-Binding Protein Modulates Circadian Gene Expression Posttranscriptionally, 10.1126/science.1217726
Mukherji Atish, Kobiita Ahmad, Ye Tao, Chambon Pierre, Homeostasis in Intestinal Epithelium Is Orchestrated by the Circadian Clock and Microbiota Cues Transduced by TLRs, 10.1016/j.cell.2013.04.020
Nguyen K. D., Fentress S. J., Qiu Y., Yun K., Cox J. S., Chawla A., Circadian Gene Bmal1 Regulates Diurnal Oscillations of Ly6Chi Inflammatory Monocytes, 10.1126/science.1240636
Nicodeme Edwige, Jeffrey Kate L., Schaefer Uwe, Beinke Soren, Dewell Scott, Chung Chun-wa, Chandwani Rohit, Marazzi Ivan, Wilson Paul, Coste Hervé, White Julia, Kirilovsky Jorge, Rice Charles M., Lora Jose M., Prinjha Rab K., Lee Kevin, Tarakhovsky Alexander, Suppression of inflammation by a synthetic histone mimic, 10.1038/nature09589
Ohno T., Onishi Y., Ishida N., A novel E4BP4 element drives circadian expression of mPeriod2, 10.1093/nar/gkl868
Ostuni Renato, Piccolo Viviana, Barozzi Iros, Polletti Sara, Termanini Alberto, Bonifacio Silvia, Curina Alessia, Prosperini Elena, Ghisletti Serena, Natoli Gioacchino, Latent Enhancers Activated by Stimulation in Differentiated Cells, 10.1016/j.cell.2012.12.018
Peek Clara Bien, Levine Daniel C., Cedernaes Jonathan, Taguchi Akihiko, Kobayashi Yumiko, Tsai Stacy J., Bonar Nicolle A., McNulty Maureen R., Ramsey Kathryn Moynihan, Bass Joseph, Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle, 10.1016/j.cmet.2016.09.010
Beg Amer A., Sha William C., Bronson Roderick T., Ghosh Sankar, Baltimore David, Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB, 10.1038/376167a0
Perelis M., Marcheva B., Moynihan Ramsey K., Schipma M. J., Hutchison A. L., Taguchi A., Peek C. B., Hong H., Huang W., Omura C., Allred A. L., Bradfield C. A., Dinner A. R., Barish G. D., Bass J., Pancreatic cell enhancers regulate rhythmic transcription of genes controlling insulin secretion, 10.1126/science.aac4250
Ramsey K. M., Yoshino J., Brace C. S., Abrassart D., Kobayashi Y., Marcheva B., Hong H.-K., Chong J. L., Buhr E. D., Lee C., Takahashi J. S., Imai S.-i., Bass J., Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis, 10.1126/science.1171641
Rao N. A. S., McCalman M. T., Moulos P., Francoijs K.-J., Chatziioannou A., Kolisis F. N., Alexis M. N., Mitsiou D. J., Stunnenberg H. G., Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes, 10.1101/gr.118042.110
Raskatov J. A., Meier J. L., Puckett J. W., Yang F., Ramakrishnan P., Dervan P. B., Modulation of NF- B-dependent gene transcription using programmable DNA minor groove binders, 10.1073/pnas.1118506109
Rey Guillaume, Cesbron François, Rougemont Jacques, Reinke Hans, Brunner Michael, Naef Felix, Genome-Wide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver, 10.1371/journal.pbio.1000595
Shimomura Kazuhiro, Kumar Vivek, Koike Nobuya, Kim Tae-Kyung, Chong Jason, Buhr Ethan D, Whiteley Andrew R, Low Sharon S, Omura Chiaki, Fenner Deborah, Owens Joseph R, Richards Marc, Yoo Seung-Hee, Hong Hee-Kyung, Vitaterna Martha H, Bass Joseph, Pletcher Mathew T, Wiltshire Tim, Hogenesch John, Lowrey Phillip L, Takahashi Joseph S, Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice, 10.7554/elife.00426
Siepka Sandra M., Takahashi Joseph S., Methods to Record Circadian Rhythm Wheel Running Activity in Mice, Methods in Enzymology (2005) ISBN:9780121827984 p.230-239, 10.1016/s0076-6879(05)93008-5
Spengler M. L., Kuropatwinski K. K., Comas M., Gasparian A. V., Fedtsova N., Gleiberman A. S., Gitlin I. I., Artemicheva N. M., Deluca K. A., Gudkov A. V., Antoch M. P., Core circadian protein CLOCK is a positive regulator of NF- B-mediated transcription, 10.1073/pnas.1206274109
Tamayo Alfred G, Duong Hao A, Robles Maria S, Mann Matthias, Weitz Charles J, Histone monoubiquitination by Clock–Bmal1 complex marks Per1 and Per2 genes for circadian feedback, 10.1038/nsmb.3076
Brown Jonathan D., Lin Charles Y., Duan Qiong, Griffin Gabriel, Federation Alexander J., Paranal Ronald M., Bair Steven, Newton Gail, Lichtman Andrew H., Kung Andrew L., Yang Tianlun, Wang Hong, Luscinskas Francis W., Croce Kevin J., Bradner James E., Plutzky Jorge, NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis, 10.1016/j.molcel.2014.08.024
Tong Xin, Muchnik Marina, Chen Zheng, Patel Manish, Wu Nan, Joshi Shree, Rui Liangyou, Lazar Mitchell A., Yin Lei, Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding, 10.1074/jbc.m110.172866
Trott Alexandra J., Menet Jerome S., Regulation of circadian clock transcriptional output by CLOCK:BMAL1, 10.1371/journal.pgen.1007156
Valekunja Utham K., Edgar Rachel S., Oklejewicz Malgorzata, van der Horst Gijsbertus T. J., O’Neill John S., Tamanini Filippo, Turner Daniel J., Reddy Akhilesh B., Histone methyltransferase MLL3 contributes to genome-scale circadian transcription, 10.1073/pnas.1214168110
Vollmers Christopher, Schmitz Robert J., Nathanson Jason, Yeo Gene, Ecker Joseph R., Panda Satchidananda, Circadian Oscillations of Protein-Coding and Regulatory RNAs in a Highly Dynamic Mammalian Liver Epigenome, 10.1016/j.cmet.2012.11.004
Wang Jingxin, Jacob Naduparambil K, Ladner Katherine J, Beg Amer, Perko James D, Tanner Stephan M, Liyanarachchi Sandya, Fishel Richard, Guttridge Denis C, RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair, 10.1038/embor.2009.197
Wang Yuhao, Kuang Zheng, Yu Xiaofei, Ruhn Kelly A., Kubo Masato, Hooper Lora V., The intestinal microbiota regulates body composition through NFIL3 and the circadian clock, 10.1126/science.aan0677
Wuarin Jérôme, Schibler Ueli, Expression of the liver-enriched transcriptional activator protein DBP follows a stringent circadian rhythm, 10.1016/0092-8674(90)90421-a
Buhr E. D., Yoo S.-H., Takahashi J. S., Temperature as a Universal Resetting Cue for Mammalian Circadian Oscillators, 10.1126/science.1195262
Yoo S.-H., Ko C. H., Lowrey P. L., Buhr E. D., Song E.-j., Chang S., Yoo O. J., Yamazaki S., Lee C., Takahashi J. S., A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo, 10.1073/pnas.0409763102
Yu X., Rollins D., Ruhn K. A., Stubblefield J. J., Green C. B., Kashiwada M., Rothman P. B., Takahashi J. S., Hooper L. V., TH17 Cell Differentiation Is Regulated by the Circadian Clock, 10.1126/science.1243884
Yu Xiaofei, Wang Yuhao, Deng Mi, Li Yun, Ruhn Kelly A, Zhang Cheng Cheng, Hooper Lora V, The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor, 10.7554/elife.04406
Zhang Yong, Liu Tao, Meyer Clifford A, Eeckhoute Jérôme, Johnson David S, Bernstein Bradley E, Nussbaum Chad, Myers Richard M, Brown Myles, Li Wei, Liu X Shirley, Model-based Analysis of ChIP-Seq (MACS), 10.1186/gb-2008-9-9-r137
Zhang Eric E., Liu Andrew C., Hirota Tsuyoshi, Miraglia Loren J., Welch Genevieve, Pongsawakul Pagkapol Y., Liu Xianzhong, Atwood Ann, Huss Jon W., Janes Jeff, Su Andrew I., Hogenesch John B., Kay Steve A., A Genome-wide RNAi Screen for Modifiers of the Circadian Clock in Human Cells, 10.1016/j.cell.2009.08.031
Zhang Guo, Li Juxue, Purkayastha Sudarshana, Tang Yizhe, Zhang Hai, Yin Ye, Li Bo, Liu Gang, Cai Dongsheng, Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH, 10.1038/nature12143
Zhang Yuxiang, Fang Bin, Damle Manashree, Guan Dongyin, Li Zhenghui, Kim Yong Hoon, Gannon Maureen, Lazar Mitchell A., HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms, 10.1101/gad.281972.116
Zhang Qian, Lenardo Michael J., Baltimore David, 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology, 10.1016/j.cell.2016.12.012
Cai Dongsheng, Frantz J.Daniel, Tawa Nicholas E., Melendez Peter A., Oh Byung-Chul, Lidov Hart G.W., Hasselgren Per-Olof, Frontera Walter R., Lee Jongsoon, Glass David J., Shoelson Steven E., IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice, 10.1016/j.cell.2004.09.027
Cai Dongsheng, Yuan Minsheng, Frantz Daniel F, Melendez Peter A, Hansen Lone, Lee Jongsoon, Shoelson Steven E, Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB, 10.1038/nm1166
Bibliographic reference
Hong, Hee-Kyung ; Maury, Eléonore ; Ramsey, Kathryn Moynihan ; Perelis, Mark ; Marcheva, Biliana ; et. al. Requirement for NF-κB in maintenance of molecular and behavioral circadian rhythms in mice.. In: Genes & development, Vol. 32, no.21-22, p. 1367-1379 (2018)