Unravelling the networks that regulate seasonal rhythmicity in the epigenome

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Two interacting rhythmical processes dominate the biology of most organisms on earth. The best studied is the circadian clock, which this has evolved to match the 24h rotation of earth. The second is the circannual clock driving ca 1-year rhythms, which has evolved in many life-forms to meet the profound environmental challenges of a seasonal planet. Although the two clock-work systems are interlocked, the precise mechanisms by which the circadian clock contributes to a seasonal response are yet to be established in any animal species, nor do we know how long-term circannual rhythm generation occurs.The seasonal and circannual timing mechanisms have been studied in sheep. Our work and others has defined how the nocturnal hormone melatonin is used by the neuroendocrine system to provide an internal representation of external photoperiod, driving seasonal reproductive and metabolic responses. A key site of action is the pituitary gland, called pars tuberalis (PT), in a region immediately adjacent to the hypothalamus, where a local circadian clock-gene rhythm is entrained each night by the daily melatonin hormone signal in specialized thyroid-stimulating hormone (TSH) expressing cells. These PT thyrotrophs have been termed "calendar cells". Here, a key transcriptional co-activator (EYA3) is rhythmically regulated, and on long summer photoperiods (LP) is strongly augmented, leading to expression of PT TSH, which activates TSH-receptors and thyroid hormone (TH) metabolism in the adjacent hypothalamus. The TH-dependency for the seasonal response is a conserved feature of the biology of vertebrate species. We have now shown that hormone packaging protein (CHGA) is induced on short winter photoperiods (SP) and that specialised cells within the PT flip from a CHGA to an EYA3 state (binary switching) over the circannual cycle.Our goal is to discover whether an "epigenetic" process underpins this binary switch and whether this switch drives long-term rhythm generation. Epigenetics is defined as the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states without changes to DNA sequence. It involves modification of histone proteins around which DNA is wrapped, and also the chemical nature (methylation) of one of the DNA nucleotides (cytosine). Our work builds in part on recently tested theoretical models developed by plant scientists studying vernalisation, which has revealed a critical role for histone-modifying enzyme complex (polycomb repressor-2, PRC2) in providing a memory of winter cold-exposure. PRC2 represses gene expression by acting on histone-3 proteins. A key element of the PRC2 complex (EZH2) is activated on LP, and we will test whether this is involved in a global suppression of SP-expressed genes, including CHGA. We now have exciting new evidence that EZH2 also activates EYA3 on LP, via the circadian clock. This leads us to the hypothesis that chromatin modifying enzymes act as binary switches, activating LP-genes, and suppressing SP-genes. This could be the long-predicted biochemical switch mechanism driving circannual cycles in vertebrates. We investigate this switch mechanism in cell models, and also using cells and tissues from sheep over the circannual cycle. This will include studies of how protein modifications and partners of EZH2 are involved. This will allow us to test this hypothesis that changes in histone-3 protein methylation (driven by EZH2) drives the circannual cycle by mapping these to underlying changes the PT. Finally, we will combine our findings with existing genomic data sets for domesticated and wild sheep breeds, and establish whether genetic circuits driving timing have been selected in course of domestication. Thus, we aim to unravel the central pathways driving the seasonal rhythm of life on our planet.