@article{890770332cbe48a692058bbf20b67dab,
title = "Defining the Independence of the Liver Circadian Clock",
abstract = "Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function. A autonomous branch of the liver circadian clock is independent from all other clocks yet still dependent on the light-dark cycle.",
keywords = "autonomous, bmal1, chromatin, circadian, clock, diurnal physiology, epigenetics, light, metabolism, systemic signaling",
author = "Koronowski, {Kevin B.} and Kenichiro Kinouchi and Welz, {Patrick Simon} and Smith, {Jacob G.} and Zinna, {Valentina M.} and Jiejun Shi and Muntaha Samad and Siwei Chen and Magnan, {Christophe N.} and Kinchen, {Jason M.} and Wei Li and Pierre Baldi and Benitah, {Salvador Aznar} and Paolo Sassone-Corsi",
note = "Funding Information: P.-S.W. generated Liver-RE mice. We thank all members of the Sassone-Corsi lab for discussions and support. We thank Melanie Oakes, Seung-Ah Chung, and Valentina Ciobanu of Genomics High-Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) at UC Irvine (NIH 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01). The European Research Council (ERC) and the Spanish Ministry of Economy and Development and IRB-Barcelona (recipient of Severo Ochoa Award of Excellence from MINECO [Government of Spain]) supported the lab of S.A.B. P.-S.W. was supported by EMBO long-term fellowship and Ayudas Juan de la Cierva fellowship (MINECO). V.M.Z. received financial support by “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence and “la Caixa” Foundation, Barcelona (ID 100010434, code LCF/BQ/IN17/11620018). P.S.-C.{\textquoteright}s lab is supported by NIH grants R21DK114652 and R21AG053592 and a Challenge Grant of the Novo Nordisk Foundation (NNF-202585). W.L.{\textquoteright}s lab is supported by R01 CA193466 and R01 HG007538. K.B.K. is supported by NIH-NINDS T32 5T32NS045540. K.K. was supported by a fellowship from Japan Society for the Promotion of Science (JSPS). P.B.{\textquoteright}s lab was supported by the grants NIH GM123558 and DARPA D17AP00002 with computing support by Yuzo Kanomata. P.-S.W. and S.A.B. generated the Liver-RE model. K.B.K. K.K. P.-S.W. W.L. P.B. S.A.B. and P.S.-C. designed the study. K.B.K. K.K. P.-S.W. V.M.Z. and J.G.S. conducted experiments and collected data. K.B.K. K.K. S.C. M.S. J.S. J.M.K. C.N.M. and P.B. performed bioinformatic analyses. K.B.K. K.K. J.G.S. and P.S.-C. wrote the paper with input from all authors. J.M.K. is an employee of Metabolon (no role in the study design). Funding Information: P.-S.W. generated Liver-RE mice. We thank all members of the Sassone-Corsi lab for discussions and support. We thank Melanie Oakes, Seung-Ah Chung, and Valentina Ciobanu of Genomics High-Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203)at UC Irvine (NIH 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01). The European Research Council (ERC)and the Spanish Ministry of Economy and Development and IRB-Barcelona (recipient of Severo Ochoa Award of Excellence from MINECO [Government of Spain])supported the lab of S.A.B. P.-S.W. was supported by EMBO long-term fellowship and Ayudas Juan de la Cierva fellowship (MINECO). V.M.Z. received financial support by “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence and “la Caixa” Foundation, Barcelona (ID 100010434, code LCF/BQ/IN17/11620018). P.S.-C.{\textquoteright}s lab is supported by NIH grants R21DK114652 and R21AG053592 and a Challenge Grant of the Novo Nordisk Foundation (NNF-202585). W.L.{\textquoteright}s lab is supported by R01 CA193466 and R01 HG007538. K.B.K. is supported by NIH-NINDS T32 5T32NS045540. K.K. was supported by a fellowship from Japan Society for the Promotion of Science (JSPS). P.B.{\textquoteright}s lab was supported by the grants NIH GM123558 and DARPA D17AP00002 with computing support by Yuzo Kanomata. P.-S.W. and S.A.B. generated the Liver-RE model. K.B.K. K.K. P.-S.W. W.L. P.B. S.A.B. and P.S.-C. designed the study. K.B.K. K.K. P.-S.W. V.M.Z. and J.G.S. conducted experiments and collected data. K.B.K. K.K. S.C. M.S. J.S. J.M.K. C.N.M. and P.B. performed bioinformatic analyses. K.B.K. K.K. J.G.S. and P.S.-C. wrote the paper with input from all authors. J.M.K. is an employee of Metabolon (no role in the study design). Funding Information: P.-S.W. generated Liver-RE mice. We thank all members of the Sassone-Corsi lab for discussions and support. We thank Melanie Oakes, Seung-Ah Chung, and Valentina Ciobanu of Genomics High-Throughput Facility Shared Resource of the Cancer Center Support Grant ( CA-62203 ) at UC Irvine ( NIH 1S10RR025496-01 , 1S10OD010794-01 , and 1S10OD021718-01 ). The European Research Council (ERC) and the Spanish Ministry of Economy and Development and IRB-Barcelona (recipient of Severo Ochoa Award of Excellence from MINECO [Government of Spain]) supported the lab of S.A.B. P.-S.W. was supported by EMBO long-term fellowship and Ayudas Juan de la Cierva fellowship (MINECO). V.M.Z. received financial support by “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence and “la Caixa” Foundation , Barcelona (ID 100010434, code LCF/BQ/IN17/11620018 ). P.S.-C.{\textquoteright}s lab is supported by NIH grants R21DK114652 and R21AG053592 and a Challenge Grant of the Novo Nordisk Foundation ( NNF-202585 ). W.L.{\textquoteright}s lab is supported by R01 CA193466 and R01 HG007538 . K.B.K. is supported by NIH-NINDS T32 5T32NS045540 . K.K. was supported by a fellowship from Japan Society for the Promotion of Science (JSPS). P.B.{\textquoteright}s lab was supported by the grants NIH GM123558 and DARPA D17AP00002 with computing support by Yuzo Kanomata. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "30",
doi = "10.1016/j.cell.2019.04.025",
language = "English (US)",
volume = "177",
pages = "1448--1462.e14",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}