The circadian rhythm-related aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) gene has been identified as a candidate gene for the murine type 1 diabetes locus Idd6.3. Previous studies suggested a role in expansion of CD4 + CD252 T cells, and this then creates an imbalance in the ratio between T-effector and CD4 The murine type 1 diabetes (T1D) locus Idd6 is 1 of ;40 genetic loci identified in the NOD mouse (1). The Idd6 candidate region (2), showing resistance to the spontaneous development of diabetes, overlaps with the candidate region for the resistance of immature T cells to dexamethasone (3-5) and for the control of low rates of proliferation in immature NOD thymocytes (6). Idd6 controls the activity of regulatory CD4 + T cells and invariant natural killer T cells (7,8).Previous research has also focused on the identification of candidate genes and the underlying molecular networks (9-13). The analysis of three NOD.C3H subcongenic strains (6.VIIIa, 6.VIIIb, and 6.VIIIc) derived from the original 6.VIII congenic strain showed the presence of at least three diabetes-related subloci contributing to the overall T1D resistance (Idd6.1, Idd6.2, Idd6.3), but Idd6.3 alone controls the suppressive activity of splenocytes (10).Transcription and sequence analysis revealed aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) as candidate gene within Idd6.3. Arntl2 encodes a basic helix-loop-helix/Per-Arnt-Sim transcription factor controlling the circadian rhythm. Arntl2 is upregulated in the spleen and thymus of mice carrying C3H alleles at Idd6.3 compared with mice carrying NOD alleles at the locus. In addition, several polymorphism and different splice forms were identified when comparing the gene and its transcripts in C3H and NOD strains (10). Diabetes incidence is increased by Arntl2 mRNA interference in Idd6 congenic mice concomitant with an increase in CD4 + T cells and a decrease in regulatory CD4 + CD25 + T cells in the peripheral immune system (14). In addition, upregulation of cellular Arntl2 levels correlates with inhibited CD4 + T-cell proliferation and their decreased diabetogenic activity (15).The current study addresses transcriptional changes related to Arntl2 expression in CD4 + T cells. We show that Arntl2 and Idd6.3 control the expression of the interleukin 21 (IL21) gene (Il21) and the number of IL21-producing cells. The promoter of Il21, a gene that codes for an important cytokine involved in the proliferation of T cells, is directly targeted by ARNTL2 in an allele-specific manner. We propose that the circadian rhythm-related Arntl2 gene has specific functions in regulating cytokines involved in T1D.
Recent gene association and functional studies have proven the implication of several circadian rhythm-related genes in diabetes. Diabetes has been related to variation in central circadian regulation and peripheral oscillation. Different transcriptional regulators have been identified. Circadian genes are clearly implicated in metabolic pathways, pancreatic function and in type 2 diabetes. Much less evidence has been shown for the link between circadian regulation and type 1 diabetes. The hypothesis that circadian genes are involved in type 1 diabetes is reinforced by findings that the immune system undergoes circadian variation and that several autoimmune diseases are associated with circadian genes. Recent findings in the non-obese diabetic mouse model pinpoint to specific mechanisms controlling type 1 diabetes by the clock-related gene Arntl2 in the immune system. Keywords: circadian rhythm, cytokine, immune system, transcription factor, type 1 diabetes Date submitted 10 April 2015; date of final acceptance 5 May 2015 Circadian Genes and DiabetesThere is growing evidence about the implication of the circadian rhythm in diabetes development [1]. Studies in mice have shown that the disruption of circadian rhythms can accelerate diabetes and -cell loss [2]. In humans a link between the central circadian rhythm regulation and glucose homeostasis has been suggested by findings such as the polymorphism in MTNR1B, encoding the melatonin receptor 1B, that increases the risk for type 2 diabetes [3].Transcription and translation of core clock components circadian locomotor output cycles kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like 1 (ARNTL1), aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2), period circadian proteins (PER1, PER2, PER3) and Cryptochromes (CRY1 and CRY2) play a pivotal role in rhythm generation in the suprachiasmatic nucleus, which is the site of the master circadian oscillator in mammals, but also in the control of peripheral oscillations.The direct relation of CLOCK-related genes in diabetes has already been shown [4]. ARNTL1, which is also called brain and muscle ARNT-like 1 (BMAL1) or member of PAS superfamily 3 (MOP3), has been genetically linked to hypertension and type 2 diabetes in humans [5]. Knockout mice for Arntl1 and Clock exhibited a role for the -cell clock in coordinating insulin secretion with the sleep-wake cycle, and revealed that ablation of the pancreatic clock can trigger the onset of diabetes mellitus [6]. The major circadian pacemaker ARNTL1 has in addition been associated with susceptibility to gestational diabetes mellitus [7]. CRY, another component of the core clock, is required for the regulation of inflammatory cytokines via the NF-kappaB Other homologous genes of the family of basic helix-loophelix transcription factors, such as the dioxin-receptor encoding gene AHR [10], ARNT [11] have been associated with diabetes. The Aryl Hydrocarbon Receptor (AHR) is a cytosolic transcription factor that is normally inactive, bound to several co-cha...
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