The big picture
Over the last two decades, our lab has discovered core clock mechanisms, created datasets, built algorithms, and made databases in wide use in the circadian community and beyond. I discovered Bmal1, the master regulator of the mammalian clock, but also its paralog Bmal2, its partner Npas2, and the positive loop of the clock (1–3). Later, our lab characterized Rora/Rorb/Rorc as key regulators of Bmal1 and circadian function (4), discovered Chrono as a non-canonical repressor of Bmal1/Clock|Npas2 (5), and Kpnb1 as a required transporter of the PER/CRY complex (6). Our lab has done the definitive work on the mammalian circadian transcriptome. In 2002, we showed that ~10% of the mouse liver transcriptome was under clock control, including many key components of cellular pathways (e.g. Hmgcoa reductase) (7). Later, using high-resolution time sampling, we found 10x more clock-regulated genes and hundreds of 2nd (12 hr) and dozens of 3rd (8hr) harmonics of circadian transcription (8). We went on to show that these harmonics depend on an intact circadian clock (9). In 2014, we completed the profiling of 12 mouse organs and showed that 43% of protein-encoding genes and a majority of disease genes and drugs target clock-regulated genes (10). Along the way, we’ve developed algorithms in broad use in the circadian community such as JTK (11), PSEA (12), and MetaCycle (13). In 2017, we published CYCLOPS, an algorithm to extract periodicity from large-scale data, and applied it to thousands of human liver, brain, lung, and cancer samples (14). This year we used CYCLOPS to create a database of circadian transcriptional rhythms from 13 human organ systems (15). These latter observations have clear implications for chronotherapy, timed dosing of drugs, to improve their therapeutic index in cancer, cardiovascular disease, and many other areas.
To make this information available, with Andy Su and Angel Pizarro, we built CircaDB (16). Making data public is the right thing to do but not enough to catalyze real progress. The goal of CircaDB is to allow everyday biologists to answer simple questions like, “what genes cycle in my organ of interest?”, “where does my gene cycle”? CircaDB allows these questions to be answer quickly and effectively, with link outs to Wikipedia, HomoloGene, Refseq, etc.. We put in sensible statistical defaults, but let users select their favorite algorithm, Q-value cutoff, phase range, or download the raw data. For the bioinformaticians, we link to all of the data in the About page along with references. The database is in use by hundreds of researchers all over the world without restriction. (I am a regular user as it is the most efficient way for me to answer these types of questions too.)
References
1. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem. 1997 Mar 28;272(13):8581–8593. PMID: 9079689
2. Hogenesch JB, Gu YZ, Jain S, Bradfield CA. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc Natl Acad Sci U S A. 1998 May 12;95(10):5474–5479. PMCID: PMC20401
3. Hogenesch JB, Gu YZ, Moran SM, Shimomura K, Radcliffe LA, Takahashi JS, Bradfield CA. The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. J Neurosci. 2000 Jul 1;20(13):RC83. PMID: 10864977
4. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron. 2004 Aug 19;43(4):527–537. PMID: 15312651
5. Anafi RC, Lee Y, Sato TK, Venkataraman A, Ramanathan C, Kavakli IH, Hughes ME, Baggs JE, Growe J, Liu AC, Kim J, Hogenesch JB. Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol. 2014 Apr;12(4):e1001840. PMCID: PMC3988006
6. Lee Y, Jang AR, Francey LJ, Sehgal A, Hogenesch JB. KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. Elife [Internet]. 2015 Aug 29;4. Available from: http://dx.doi.org/10.7554/eLife.08647 PMCID: PMC4597257
7. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002 May 3;109(3):307–320. PMID: 12015981
8. Hughes ME, DiTacchio L, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S, Hogenesch JB. Harmonics of circadian gene transcription in mammals. PLoS Genet. 2009 Apr;5(4):e1000442. PMCID: PMC2654964
9. Hughes ME, Hong H-K, Chong JL, Indacochea AA, Lee SS, Han M, Takahashi JS, Hogenesch JB. Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue. PLoS Genet. 2012 Jul 26;8(7):e1002835. PMCID: PMC3405989
10. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16219–16224. PMCID: PMC4234565
11. Hughes ME, Hogenesch JB, Kornacker K. JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. J Biol Rhythms. 2010 Oct;25(5):372–380. PMCID: PMC3119870
12. Zhang R, Podtelezhnikov AA, Hogenesch JB, Anafi RC. Discovering Biology in Periodic Data through Phase Set Enrichment Analysis (PSEA). J Biol Rhythms. 2016 Jun;31(3):244–257. PMID: 26955841
13. Wu G, Anafi RC, Hughes ME, Kornacker K, Hogenesch JB. MetaCycle: an integrated R package to evaluate periodicity in large scale data. Bioinformatics. 2016 Nov 1;32(21):3351–3353. PMCID: PMC5079475
14. Anafi RC, Francey LJ, Hogenesch JB, Kim J. CYCLOPS reveals human transcriptional rhythms in health and disease. Proc Natl Acad Sci U S A. 2017 May 16;114(20):5312–5317. PMCID: PMC5441789
15. Ruben MD, Wu G, Smith DF, Schmidt RE, Francey LJ, Lee YY, Anafi RC, Hogenesch JB. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci Transl Med [Internet]. 2018 Sep 12;10(458). Available from: http://dx.doi.org/10.1126/scitranslmed.aat8806 PMID: 30209245
16. Pizarro A, Hayer K, Lahens NF, Hogenesch JB. CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res. 2013 Jan;41(Database issue):D1009–13. PMCID: PMC3531170