1. Introduction

Circadian rhythms function in most living organisms and govern many behavioural and biochemical processes with 24-h periodicity regardless of changes in the cellular environment. This is closely associated with the natural rhythm of the sun, which provides light and heat with 24-h periodicity. The master clock that generates circadian rhythms in mammals is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is governed by bluelight sensing in eyes. Peripheral organs also contain molecular clocks. These biological clocks control all aspects of physiology such as sleep-wake cycles, body temperature, hormone secretion, blood pressure and metabolism [1]. Biological clocks oscillate via a mechanism

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

based on interlocking transcriptional-translational feedback loops that have both positive and negative elements. The circadian oscillator orchestrates the rhythmic mRNA expression and output of hundreds or thousands of clock-controlled genes (CCG) that temporally coordinate many cellular functions [2]. Circadian transcriptional regulators are apparently involved in the initial stages of RNA polymerase II recruitment and initiation, as well as the histone modifications associated with these events to set the stage for gene expression [3]. The methylation of cytosine on CpG dinucleotides, which is also epigenetic regulation of gene expression, either directly interferes with the binding of transcriptional regulators or indirectly inactivates a gene by modulating chromatin to a repressive structure. About 43% of all protein-encoding genes in mice exhibit circadian rhythms of mRNA abundance somewhere in the body, largely in an organ-specific manner [4]. The temporal coordination of cellular functions is lost when circadian rhythms are disrupted by age, the environment or genetic mutation, with deleterious effects on health. For instance, the adrenal steroid hormone glucocorticoid that controls various physiological processes, such as metabolism, the immune response, cardiovascular activity and brain function, is under the control of the circadian clock [5], implying that several diseases are closely associated with disrupted circadian rhythms.

amino acid-rich bZIP (PAR-bZIP) transcription factor family, including DBP, E4BP4, HLF and TEF [11, 12]. A combination of three binding elements, E-boxes, ROREs and D-boxes, coordinates CCG transcription. Figure 1 shows that most core clock proteins including BMAL1, CLOCK, PER, CRY, REB-ERB, ROR and E4BP4 bind to many thousands of sites in the genome

Epigenetic Modulation of Circadian Rhythms: *Bmal1* Gene Regulation

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Transcriptional regulation initially requires the coordinated control of chromatin and the genome structure [3]. In general, genetic information is packed into the chromatin structure, of which the nucleosome is the most basic unit; it determines the large-scale chromatin structure as a building block and influences transcription. Eukaryotic promoter regions are thought to have inactive states, assured by the tendency of nucleosomes to inhibit transcription by protecting protein-DNA interaction. Therefore, chromatin remodelling and loosening of the nucleosomal barrier including histone tail modifications are key steps in circadian modifications followed by sequence-specific, transcription factor binding that regulates gene expressions [14]. Distinct chromatin states are determined by unique histone post-translational modifications. First, histone acetylation levels fluctuate rhythmically at clock gene promoters and enhancers. Specifically, acetylated histone H3 at Lys27 (H3K27ac), a marker of active enhancers, and H3 at Lys9 (H3K9ac) are rhythmic and positively correlate with clock gene expression. For example, rhythmic BMAL1-CLOCK binding and H3K9ac are required as well as rhythmic histone H3 abundance at the start site for Dbp transcription [15]. Complexes of clock proteins such as PER contain various interactive partners with known catalytic activity towards chromatin [16, 17]. The acetylation of histone H3 (at Lys9 and Lys14) at Per1, Per2 and Cry1 and of H4 at Per1 during the transcriptional activation phase has been identified [18, 19]. Rhythmic histone acetylation at clock loci is largely mediated by p300 and CBP histone

Figure 1. Hierarchical regulation mechanism of circadian transcription. E, RORE and D indicate transcription factor recogni-

in a circadian manner [13].

tion sites: E-box, RORE and D-box, respectively.

2.2. Epigenetic mechanism: effect of chromatin structure
