Genome-wide Expression Analysis Reveals 100 Adrenal Gland-dependent Circadian Genes in the Mouse Liver

Abstract

Recent progress in genome-wide expression analysis has identified hundreds of circadian genes not only in the suprachiasmatic nucleus (the mammalian master clock) but also in peripheral tissues, such as heart, liver and kidney of mammals. Glucocorticoid is thought to be a circadian time cue for mammalian peripheral clocks. To identify the genes of which the circadian expression is regulated by endogenous glucocorticoids, we performed DNA microarray analysis using hepatic RNA from adrenalectomized (ADX) and sham-operated mice. We identified 169 genes that fluctuated between day and night in the livers of the sham-operated mice. Among these, 100 lost circadian rhythmicity in ADX mice. These included the genes for key enzymes of liver metabolic functions, such as glucokinase, HMG-CoA reductase and glucose-6-phosphatase. The circadian expression of Lpin1, FKBP51 and S-adenosyl methionine decarboxylase was also abolished in the ADX mice. On the other hand, although the circadian expression of clock or clock-related genes, such as mPer2, DBP, E4BP4, mDec1, Usp2 and Wee1 remained almost totally intact in the liver of ADX mice, it was extremely damped in homozygous Clock mutant mice. The present findings suggested that one type of hepatic circadian genes in mice is transcriptionally regulated by core components of the circadian clock, such as CLOCK and BMAL1, and that the other depends on the adrenal gland.

Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production

“…Moreover, there exist 2 types of GC receptors with distinctive affinities and capacities, and these are believed to be differentially activated at the circadian peak and nadir of circulating ligand levels (2). The observations that the expression of at least 10% of all genes is influenced by GC (2), and that the cyclicities of some hepatic genes can be affected by an intact adrenal gland and/or GC signaling (43,44), strongly support this notion. Also, the circadian rhythm of certain discrete brain regions is dependent on GC signaling, implying that even higher brain functions can be directly influenced by the adrenal rhythm (40,45).…”

cAMP-response Element (CRE)-mediated Transcription by Activating Transcription Factor-4 (ATF4) Is Essential for Circadian Expression of the Period2 Gene

“…Circadian gene expression is caused not only by a cell-autonomous mechanism but also by time-dependent changes in extracellular stimuli (18,19). To determine whether circadian expression of the Atf4 gene is cell autonomous, we examined Atf4 mRNA levels in MEFs prepared from wild-type and Clock/ Clock mice.…”

Diurnal expression ofDnmt3bmRNA in mouse liver is regulated by feeding and hepatic clockwork

“…The previous study on the ontogeny of circadian oscillations revealing that the adult-like diurnal expression pattern of Bmal1 in rat liver starts 20 d after birth 35 coincides with our present result. The hepatic circadian clock has been found to be entrained by central signals [36][37][38] and peripheral signals of ingested nutrients. [39][40][41][42] In view of the similarities between the expression patterns of Bmal1 and Dnmt3b observed in our developmental experiment and SF Figure 3.…”