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NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1
In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory...
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Published in: | PLoS genetics 2021-11, Vol.17 (11), p.e1009933-e1009933 |
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description | In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways. |
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Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1009933</identifier><identifier>PMID: 34807912</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; ARNTL Transcription Factors - genetics ; Biology and Life Sciences ; Bioluminescence ; BMAL1 protein ; Calcium-Binding Proteins - genetics ; Cell Line, Tumor ; Chromatin ; Circadian Clocks - genetics ; Circadian rhythm ; Circadian Rhythm - genetics ; Circadian rhythms ; Clock gene ; CLOCK Proteins - genetics ; Cryptochromes ; Cryptochromes - genetics ; Gene expression ; Gene Expression Regulation, Developmental - genetics ; Humans ; Immunoprecipitation ; Independent sample ; Inflammation ; Inflammation - genetics ; Inflammation - pathology ; Kinases ; Locomotor activity ; Mammals ; NF-kappa B - genetics ; NF-κB protein ; Phenotypes ; Physiology ; RelA protein ; Research and analysis methods ; Suprachiasmatic nucleus ; Suprachiasmatic Nucleus - metabolism ; Transcription Factor RelA - genetics ; Transcription factors</subject><ispartof>PLoS genetics, 2021-11, Vol.17 (11), p.e1009933-e1009933</ispartof><rights>2021 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Shen et al 2021 Shen et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-ebd8681aa2e5f3f64268a2c8c8cc1adbb0e859030b5bd6ae26c8925fb7958fb33</citedby><cites>FETCH-LOGICAL-c526t-ebd8681aa2e5f3f64268a2c8c8cc1adbb0e859030b5bd6ae26c8925fb7958fb33</cites><orcidid>0000-0002-1684-4780 ; 0000-0003-2129-4047 ; 0000-0002-1224-9415 ; 0000-0003-1927-0900 ; 0000-0002-4121-1467</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2610942187/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2610942187?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34807912$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kramer, Achim</contributor><creatorcontrib>Shen, Yang</creatorcontrib><creatorcontrib>Endale, Mehari</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Morris, Andrew R</creatorcontrib><creatorcontrib>Francey, Lauren J</creatorcontrib><creatorcontrib>Harold, Rachel L</creatorcontrib><creatorcontrib>Hammers, David W</creatorcontrib><creatorcontrib>Huo, Zhiguang</creatorcontrib><creatorcontrib>Partch, Carrie L</creatorcontrib><creatorcontrib>Hogenesch, John B</creatorcontrib><creatorcontrib>Wu, Zhao-Hui</creatorcontrib><creatorcontrib>Liu, Andrew C</creatorcontrib><title>NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways.</description><subject>Animals</subject><subject>ARNTL Transcription Factors - genetics</subject><subject>Biology and Life Sciences</subject><subject>Bioluminescence</subject><subject>BMAL1 protein</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Cell Line, Tumor</subject><subject>Chromatin</subject><subject>Circadian Clocks - genetics</subject><subject>Circadian rhythm</subject><subject>Circadian Rhythm - genetics</subject><subject>Circadian rhythms</subject><subject>Clock gene</subject><subject>CLOCK Proteins - genetics</subject><subject>Cryptochromes</subject><subject>Cryptochromes - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental - genetics</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Independent sample</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - pathology</subject><subject>Kinases</subject><subject>Locomotor activity</subject><subject>Mammals</subject><subject>NF-kappa B - genetics</subject><subject>NF-κB protein</subject><subject>Phenotypes</subject><subject>Physiology</subject><subject>RelA protein</subject><subject>Research and analysis methods</subject><subject>Suprachiasmatic nucleus</subject><subject>Suprachiasmatic Nucleus - metabolism</subject><subject>Transcription Factor RelA - genetics</subject><subject>Transcription factors</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1DAUtRCIloE_QBCJDZsMfsfeILVVC5UG2MDaunacGQ9JPNgJiF_rR_BNZGbSqkXIC1_5nnN87tVB6CXBS8Iq8m4bx9RDu9ytfb8kGGvN2CN0SoRgZcUxf3yvPkHPct5izITS1VN0wrjClSb0FLnPV-Wfm_Oii3Vogs_FsPFFB10HbYC-cCE5qA9VG933qZviuN4UoR98AjeE2Be_wrA50FxMfsbtUhx86IvzT2cr8hw9aaDN_sV8L9C3q8uvFx_L1ZcP1xdnq9IJKofS21pJRQCoFw1rJKdSAXVqOo5AbS32SmjMsBW2luCpdEpT0dhKC9VYxhbo9VF318Zs5v1kQyXBmlOiqglxfUTUEbZml0IH6beJEMzhIaa1gTQE13qjHKO0aaDWWPBJX2PMLVRSaGuVnBa7QO_n30bb-dr5fkjQPhB92OnDxqzjT6MkV5OjSeDtLJDij9HnwXQhO9-20Ps47n1jMiG53vt-8w_0_9PxI8qlmHPyzZ0Zgs0-M7css8-MmTMz0V7dH-SOdBsS9hcd38Cn</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Shen, Yang</creator><creator>Endale, Mehari</creator><creator>Wang, Wei</creator><creator>Morris, Andrew R</creator><creator>Francey, Lauren J</creator><creator>Harold, Rachel L</creator><creator>Hammers, David W</creator><creator>Huo, Zhiguang</creator><creator>Partch, Carrie L</creator><creator>Hogenesch, John B</creator><creator>Wu, Zhao-Hui</creator><creator>Liu, Andrew C</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-1684-4780</orcidid><orcidid>https://orcid.org/0000-0003-2129-4047</orcidid><orcidid>https://orcid.org/0000-0002-1224-9415</orcidid><orcidid>https://orcid.org/0000-0003-1927-0900</orcidid><orcidid>https://orcid.org/0000-0002-4121-1467</orcidid></search><sort><creationdate>20211101</creationdate><title>NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1</title><author>Shen, Yang ; Endale, Mehari ; Wang, Wei ; Morris, Andrew R ; Francey, Lauren J ; Harold, Rachel L ; Hammers, David W ; Huo, Zhiguang ; Partch, Carrie L ; Hogenesch, John B ; Wu, Zhao-Hui ; Liu, Andrew C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-ebd8681aa2e5f3f64268a2c8c8cc1adbb0e859030b5bd6ae26c8925fb7958fb33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>ARNTL Transcription Factors - 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Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. 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subjects | Animals ARNTL Transcription Factors - genetics Biology and Life Sciences Bioluminescence BMAL1 protein Calcium-Binding Proteins - genetics Cell Line, Tumor Chromatin Circadian Clocks - genetics Circadian rhythm Circadian Rhythm - genetics Circadian rhythms Clock gene CLOCK Proteins - genetics Cryptochromes Cryptochromes - genetics Gene expression Gene Expression Regulation, Developmental - genetics Humans Immunoprecipitation Independent sample Inflammation Inflammation - genetics Inflammation - pathology Kinases Locomotor activity Mammals NF-kappa B - genetics NF-κB protein Phenotypes Physiology RelA protein Research and analysis methods Suprachiasmatic nucleus Suprachiasmatic Nucleus - metabolism Transcription Factor RelA - genetics Transcription factors |
title | NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1 |
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