Extensive and divergent circadian gene expression in liver and heart

Storch, Kai‐Florian; Lipan, Ovidiu; Leykin, Igor; Viswanathan, N.; Davis, Fred C.; Wong, Wing Hung; Weitz, Charles J.

doi:10.1038/nature744

Cited by 1,393 publications

(1,137 citation statements)

References 28 publications

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“…20 Though subtle, this could be quite significant as 5-9% of the liver transcriptome and 420% of its secreted proteome are under CR control. 40,41 We traced back higher DBP mRNA levels to higher protein (not mRNA) levels of its transcriptional regulator ARNTL in HET livers. This latter result suggests that hepatic ARNTL is directly or indirectly regulated at the posttranslational level by ubiquitin-editing A20, which would agree with ARNTL incurring posttranslational sumoylation and ubiquitination, 42 and its protein levels being modulated by proteasomal activity.…”

Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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“…DNA microarray studies in mice indicate that ~5-9% of the genome, excluding genes involved in the core clock loop, are under circadian control (Akhtar et al, 2002;Panda et al, 2002;Storch et al, 2002). However, these so-called clock-controlled genes (CCGs) differ among tissues, with any two tissues likely sharing less than 10% of CCGs under circadian control.…”

Section: Direct and Indirect Transcriptional Control As A Clock Outputmentioning

confidence: 99%

The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

131

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Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between "clock cells" and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized. KeywordsCircadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic Circadian aspects of reproductionThe importance of circadian (about a day) timing in hormone production/secretion has been known since the 1950s when Everett and Sawyer determined that a stimulatory signal occurring during a narrow temporal window on the afternoon of proestrus is necessary for induction of ovulation later that night (Everett and Sawyer, 1950). Such close temporal organization is important for successful reproduction, as numerous hormone-dependent behavioral and physiological processes must be coordinated. If optimal temporal relationships are disrupted, pronounced deficits in fertility can result. For example, ovulation, behavioral estrus, fertilization, and pregnancy maintenance require a specific

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“…Rhythmic mRNA expression has mostly been characterized by analyzing temporal changes of steady-state mRNA levels, using techniques such as microarrays (e.g., McDonald and Rosbash, 2001; Panda et al, 2002; Storch et al, 2002) and more recently high-throughput sequencing (Hughes et al, 2012). It is generally assumed that these rhythms in mRNA expression directly result from temporal changes in transcription.…”

Section: Introductionmentioning

confidence: 99%

Nascent-Seq reveals novel features of mouse circadian transcriptional regulation

Menet

Rodriguez

Abruzzi

et al. 2012

eLife

295

405

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A substantial fraction of the metazoan transcriptome undergoes circadian oscillations in many cells and tissues. Based on the transcription feedback loops important for circadian timekeeping, it is commonly assumed that this mRNA cycling reflects widespread transcriptional regulation. To address this issue, we directly measured the circadian dynamics of mouse liver transcription using Nascent-Seq (genome-wide sequencing of nascent RNA). Although many genes are rhythmically transcribed, many rhythmic mRNAs manifest poor transcriptional rhythms, indicating a prominent contribution of post-transcriptional regulation to circadian mRNA expression. This analysis of rhythmic transcription also showed that the rhythmic DNA binding profile of the transcription factors CLOCK and BMAL1 does not determine the transcriptional phase of most target genes. This likely reflects gene-specific collaborations of CLK:BMAL1 with other transcription factors. These insights from Nascent-Seq indicate that it should have broad applicability to many other gene expression regulatory issues.DOI: http://dx.doi.org/10.7554/eLife.00011.001

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Extensive and divergent circadian gene expression in liver and heart

Cited by 1,393 publications

References 28 publications

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

The regulation of neuroendocrine function: Timing is everything

Nascent-Seq reveals novel features of mouse circadian transcriptional regulation

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