General Information of the m6A Target Gene (ID: M6ATAR00199)
Target Name Brain and muscle ARNT-like 1 (Bmal1/ARNTL)
Synonyms
Basic-helix-loop-helix-PAS protein MOP3; Brain and muscle ARNT-like 1; Class E basic helix-loop-helix protein 5; bHLHe5; Member of PAS protein 3; PAS domain-containing protein 3; bHLH-PAS protein JAP3; BHLHE5; BMAL1; MOP3; PASD3
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Gene Name ARNTL
Chromosomal Location 11p15.3
Function
Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. ARNTL/BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence. CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3'. The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1. Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (By similarity). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By similarity). (Microbial infection) Regulates SARS coronavirus-2/SARS-CoV-2 entry and replication in lung epithelial cells probably through the post-transcriptional regulation of ACE2 and interferon-stimulated gene expression.
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Gene ID 406
Uniprot ID
BMAL1_HUMAN
HGNC ID
HGNC:701
Ensembl Gene ID
ENSG00000133794
KEGG ID
hsa:406
Full List of m6A Methylation Regulator of This Target Gene and Corresponding Disease/Drug Response(s)
ARNTL can be regulated by the following regulator(s), and cause disease/drug response(s). You can browse detail information of regulator(s) or disease/drug response(s).
Browse Regulator
Browse Disease
Methyltransferase-like 3 (METTL3) [WRITER]
Representative RNA-seq result indicating the expression of this target gene regulated by METTL3
Cell Line mouse embryonic stem cells Mus musculus
Treatment: METTL3-/- ESCs
Control: Wild type ESCs
GSE145309
Regulation
logFC: -1.11E+00
p-value: 1.53E-46
More Results Click to View More RNA-seq Results
In total 2 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [1]
Response Summary PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Hepatic deletion of Brain and muscle ARNT-like 1 (Bmal1/ARNTL) increases m6A mRNA methylation, particularly of PPaRalpha. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaR-Alpha m6A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases.
Target Regulation Up regulation
Responsed Disease Metabolic disorders ICD-11: 5D2Z
Pathway Response Adipocytokine signaling pathway hsa04920
Cell Process Llipid metabolism
In-vitro Model Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
In-vivo Model Liver-specific Bmal1f/f-AlbCre-knockout mice were purchased from Jackson Laboratory. C57BI/6J or Bmal1f/f-AlbCre-knockout male mice were maintained under a 12 hr light/12 hr dark (LD) cycle (ZT0 = 6 AM) and fed ad libitum with normal rodent chow (2018 Global 18% Protein diet, Envigo) and water. At 10-14 weeks of age, 10 male mice per group were sacrificed via CO2 asphyxiation at Zeitgeber Time (ZT) 0,2,6,10,12,14,18,22. In order to induce high levels of ROS in the liver, WT male mice were fasted 12 h and followed by intraperitoneal injection with 300 mg/kg APAP dissolved in PBS and re-fed.
Experiment 2 Reporting the m6A Methylation Regulator of This Target Gene [2]
Response Summary Liver-specific Mettl3 knockout mice exhibited global decrease in m6A on polyadenylated RNAs and pathologic features associated with nonalcoholic fatty liver disease. Studies in the M3LKO model indicated that METTL3 exhibits pleotropic function to maintain liver homeostasis by deregulating m6A profile and expression of the liver transcriptome. A significant decrease in total Brain and muscle ARNT-like 1 (Bmal1/ARNTL) and Clock mRNAs but an increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export.
Target Regulation Up regulation
Responsed Disease Non-alcoholic fatty liver disease ICD-11: DB92
In-vivo Model M3LKO (Mettl3fl/fl; Alb-Cre) mice were generated by crossing Mettl3fl/fl mice (provided by Dr. Jacob Hanna) with albumin-Cre mice (Jackson Laboratories, Bar Harbor, ME), and genotypes were confirmed by tail-DNA PCR using primers as previously described.
YTH domain-containing family protein 2 (YTHDF2) [READER]
Representative RNA-seq result indicating the expression of this target gene regulated by YTHDF2
Cell Line B18-hi B cell line Mus musculus
Treatment: YTHDF2 knockout B18-hi B cells
Control: Wild type B18-hi B cells
GSE189819
Regulation
logFC: -7.97E-01
p-value: 5.55E-03
More Results Click to View More RNA-seq Results
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [1]
Response Summary PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Hepatic deletion of Brain and muscle ARNT-like 1 (Bmal1/ARNTL) increases m6A mRNA methylation, particularly of PPaRalpha. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaR-Alpha m6A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases.
Target Regulation Down regulation
Responsed Disease Metabolic disorders ICD-11: 5D2Z
Pathway Response PPAR signaling pathway hsa03320
Adipocytokine signaling pathway hsa04920
Cell Process Llipid metabolism
In-vitro Model Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
In-vivo Model Liver-specific Bmal1f/f-AlbCre-knockout mice were purchased from Jackson Laboratory. C57BI/6J or Bmal1f/f-AlbCre-knockout male mice were maintained under a 12 hr light/12 hr dark (LD) cycle (ZT0 = 6 AM) and fed ad libitum with normal rodent chow (2018 Global 18% Protein diet, Envigo) and water. At 10-14 weeks of age, 10 male mice per group were sacrificed via CO2 asphyxiation at Zeitgeber Time (ZT) 0,2,6,10,12,14,18,22. In order to induce high levels of ROS in the liver, WT male mice were fasted 12 h and followed by intraperitoneal injection with 300 mg/kg APAP dissolved in PBS and re-fed.
Metabolic disorders [ICD-11: 5D2Z]
In total 2 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [1]
Response Summary PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Hepatic deletion of Brain and muscle ARNT-like 1 (Bmal1/ARNTL) increases m6A mRNA methylation, particularly of PPaRalpha. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaR-Alpha m6A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases.
Responsed Disease Metabolic disorders [ICD-11: 5D2Z]
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
Target Regulation Up regulation
Pathway Response Adipocytokine signaling pathway hsa04920
Cell Process Llipid metabolism
In-vitro Model Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
In-vivo Model Liver-specific Bmal1f/f-AlbCre-knockout mice were purchased from Jackson Laboratory. C57BI/6J or Bmal1f/f-AlbCre-knockout male mice were maintained under a 12 hr light/12 hr dark (LD) cycle (ZT0 = 6 AM) and fed ad libitum with normal rodent chow (2018 Global 18% Protein diet, Envigo) and water. At 10-14 weeks of age, 10 male mice per group were sacrificed via CO2 asphyxiation at Zeitgeber Time (ZT) 0,2,6,10,12,14,18,22. In order to induce high levels of ROS in the liver, WT male mice were fasted 12 h and followed by intraperitoneal injection with 300 mg/kg APAP dissolved in PBS and re-fed.
Experiment 2 Reporting the m6A-centered Disease Response [1]
Response Summary PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Hepatic deletion of Brain and muscle ARNT-like 1 (Bmal1/ARNTL) increases m6A mRNA methylation, particularly of PPaRalpha. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaR-Alpha m6A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases.
Responsed Disease Metabolic disorders [ICD-11: 5D2Z]
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
Target Regulation Down regulation
Pathway Response PPAR signaling pathway hsa03320
Adipocytokine signaling pathway hsa04920
Cell Process Llipid metabolism
In-vitro Model Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
In-vivo Model Liver-specific Bmal1f/f-AlbCre-knockout mice were purchased from Jackson Laboratory. C57BI/6J or Bmal1f/f-AlbCre-knockout male mice were maintained under a 12 hr light/12 hr dark (LD) cycle (ZT0 = 6 AM) and fed ad libitum with normal rodent chow (2018 Global 18% Protein diet, Envigo) and water. At 10-14 weeks of age, 10 male mice per group were sacrificed via CO2 asphyxiation at Zeitgeber Time (ZT) 0,2,6,10,12,14,18,22. In order to induce high levels of ROS in the liver, WT male mice were fasted 12 h and followed by intraperitoneal injection with 300 mg/kg APAP dissolved in PBS and re-fed.
Non-alcoholic fatty liver disease [ICD-11: DB92]
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [2]
Response Summary Liver-specific Mettl3 knockout mice exhibited global decrease in m6A on polyadenylated RNAs and pathologic features associated with nonalcoholic fatty liver disease. Studies in the M3LKO model indicated that METTL3 exhibits pleotropic function to maintain liver homeostasis by deregulating m6A profile and expression of the liver transcriptome. A significant decrease in total Brain and muscle ARNT-like 1 (Bmal1/ARNTL) and Clock mRNAs but an increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export.
Responsed Disease Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
Target Regulation Up regulation
In-vivo Model M3LKO (Mettl3fl/fl; Alb-Cre) mice were generated by crossing Mettl3fl/fl mice (provided by Dr. Jacob Hanna) with albumin-Cre mice (Jackson Laboratories, Bar Harbor, ME), and genotypes were confirmed by tail-DNA PCR using primers as previously described.
References
Ref 1 Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m(6)A mRNA Methylation. Cell Rep. 2018 Nov 13;25(7):1816-1828.e4. doi: 10.1016/j.celrep.2018.10.068.
Ref 2 METTL3 Regulates Liver Homeostasis, Hepatocyte Ploidy, and Circadian Rhythm-Controlled Gene Expression in Mice. Am J Pathol. 2022 Jan;192(1):56-71. doi: 10.1016/j.ajpath.2021.09.005. Epub 2021 Sep 29.