Fig. 1

Timeline of major findings in mammalian circadian clock research. 1920s: first long-term recordings of locomotor rhythms in rats (reviewed in [12]). 1960: Cold Spring Harbor Symposium on Biological Clocks. First observations that time of day determines susceptibility to endotoxins [13]. 1972: lesion studies show that the suprachiasmatic nucleus (SCN) of the hypothalamus regulates adrenal corticosterone and drinking behavior rhythms [14, 15]. Late 1970s and 1980s: first ENU screens for novel gene identification were performed in mammals [16]. 1984–1990: identification of the SCN as a master regulator through transplantation experiments [17, 18]. 1988: a naturally occurring circadian Tau mutation was identified in hamsters [19]. 1990s: first mammalian ENU screens for behavior, leading to the identification of the first mammalian clock gene, Clock [2]. 1995: circadian rhythms were shown to be cell-autonomous in mammals, being retained in isolated SCN neurons [20]. 1997: cloning of the Clock gene, which was shown to belong to the bHLH–PAS family of transcription factors. In the same year, the mammalian Per1 gene was also cloned, both providing entry points for identifying the mechanism of circadian rhythmicity in mammals [3, 8]. 1998–2000: Discovery of BMAL1/MOP3 as the partner of CLOCK [5, 11], repression by CRY [10] and the Per1/2-Cry1/2 feedback loop on CLOCK:BMAL1 [21]. First descriptions of circadian clocks in the periphery [22, 23]. The cloning of the hamster Tau mutant identified CK1ε as an important kinase regulating the core circadian clock [24]. 2000s: melanopsin was identified as the circadian photoreceptor in the retina [25,26,27]. 2001: first mutation in a clock gene associated with human disease [28]. 2002: first circadian transcriptomes revealed a significant subset of genes that have cyclic gene expression with a 24-h period [29,30,31]. 2004–2005: association of mutations in clock genes with impaired metabolism [32, 33]. 2011: peroxiredoxin cycles reported to be independent of transcription [34]. 2011–2012: detailed descriptions of genome-wide regulation by the clock [35,36,37,38]. 2012–2013: major advances in our understanding of the clock control of immunity [39,40,41,42]. Present day: a new layer in our understanding of genome-wide regulation by the clock through circadian chromosome organization is emerging [43,44,45]. ENU, N-ethyl-N-nitrosourea