{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:45:35Z","timestamp":1784191535614,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32172729"],"award-info":[{"award-number":["32172729"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The circadian rhythm of melatonin secretion in the pineal gland is highly conserved in vertebrates. Melatonin levels are always elevated at night. Acetylserotonin O-methyltransferase (ASMT) is the last enzyme in the regulation of melatonin biosynthesis (N-acetyl-5-hydroxytryptamine-melatonin). S-adenosylmethionine (SAM) is an important methyl donor in mammals and can be used as a substrate for the synthesis of melatonin. Methionine adenosyltransferase (MAT) catalyzes the synthesis of SAM from methionine and ATP and has a circadian rhythm. CircRNA is an emerging type of endogenous noncoding RNA with a closed loop. Whether circRNAs in the pineal gland can participate in the regulation of melatonin synthesis by binding miRNAs to target mat2a as part of the circadian rhythm is still unclear. In this study, we predicted the targeting relationship of differentially expressed circRNAs, miRNAs and mRNAs based on the results of rat pineal RNA sequencing. Mat2a siRNA transfection confirmed that mat2a is involved in the synthesis of melatonin. Circ-ERC2 and miR-125a-5p were screened out by software prediction, dual-luciferase reporter experiments, cell transfection, etc. Finally, we constructed a rat superior cervical ganglionectomy model (SCGx), and the results showed that circ-ERC2 could participate in the synthesis of melatonin through the miR-125a-5p\/MAT2A axis. The results of the study revealed that circ-ERC2 can act as a molecular sponge of miR-125a-5p to regulate the synthesis of melatonin in the pineal gland by targeting mat2a. This experiment provides a basis for research on the circadian rhythm of noncoding RNA on pineal melatonin secretion.<\/jats:p>","DOI":"10.3390\/ijms232415477","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T04:38:54Z","timestamp":1670387934000},"page":"15477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Circ-ERC2 Is Involved in Melatonin Synthesis by Regulating the miR-125a-5p\/MAT2A Axis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3410-4372","authenticated-orcid":false,"given":"Hai-Xiang","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Kun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3996-2509","authenticated-orcid":false,"given":"Fei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-4744","authenticated-orcid":false,"given":"Jia-Bao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5342-0664","authenticated-orcid":false,"given":"Yong-Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3490-0755","authenticated-orcid":false,"given":"Bao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1600-079X.2004.00196.x","article-title":"The human pineal gland and melatonin in aging and Alzheimer\u2019s disease","volume":"38","author":"Wu","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.yfrne.2004.08.001","article-title":"Human pineal physiology and functional significance of melatonin","volume":"25","author":"Macchi","year":"2004","journal-title":"Front. Neuroendocr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/B978-0-12-416021-7.00005-5","article-title":"The Pineal Gland from Development to Function","volume":"106","author":"Cau","year":"2013","journal-title":"Curr. Top Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e12753","DOI":"10.1111\/jpi.12753","article-title":"The role of homeobox gene-encoded transcription factors in regulation of phototransduction: Implementing the primary pinealocyte culture as a photoreceptor model","volume":"71","author":"Hertz","year":"2021","journal-title":"J. Pineal Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e12742","DOI":"10.1111\/jpi.12742","article-title":"A hypothetical role for autophagy during the day\/night rhythm-regulated melatonin synthesis in the rat pineal gland","volume":"71","author":"Ge","year":"2021","journal-title":"J. Pineal Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e12616","DOI":"10.1111\/jpi.12616","article-title":"The Lhx4 homeobox transcript in the rat pineal gland: Adrenergic regulation and impact on transcripts encoding melatonin-synthesizing enzymes","volume":"68","author":"Hertz","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e12450","DOI":"10.1111\/jpi.12450","article-title":"Effects of melatonin on fatty liver disease: The role of NR4A1\/DNA-PKcs\/p53 pathway, mitochondrial fission, and mitophagy","volume":"64","author":"Zhou","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1600-079X.2011.00962.x","article-title":"Melatonin and its analogs in insomnia and depression","volume":"52","author":"Cardinali","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s11154-009-9125-5","article-title":"Melatonin formation in mammals: In vivo perspectives","volume":"10","author":"Chattoraj","year":"2009","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1007\/BF01953049","article-title":"Melatonin biosynthesis in the mammalian pineal gland","volume":"45","author":"Sugden","year":"1989","journal-title":"Experientia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s00441-002-0579-y","article-title":"Control of melatonin synthesis in the mammalian pineal gland: The critical role of serotonin acetylation","volume":"309","author":"Ganguly","year":"2002","journal-title":"Cell Tissue Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1073\/pnas.141118798","article-title":"Role of a pineal cAMP-operated arylalkylamine N- acetyltransferase\/14-3-3-binding switch in melatonin synthesis","volume":"98","author":"Ganguly","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1600-079X.2005.00223.x","article-title":"N-acetyltransferase is not the rate-limiting enzyme of melatonin synthesis at night","volume":"39","author":"Liu","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/sj.mp.4002016","article-title":"Abnormal melatonin synthesis in autism spectrum disorders","volume":"13","author":"Melke","year":"2008","journal-title":"Mol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0021-9258(18)64458-8","article-title":"Purification and properties of hydroxyindole-O-methyl transferase","volume":"236","author":"Axelrod","year":"1961","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1046\/j.1471-4159.1995.65041887.x","article-title":"Nyctohemeral Rhythm in the Levels of S-Adenosylmethionine in the Rat Pineal Gland and Its Relationship to Melatonin Biosynthesis","volume":"65","author":"Sitaram","year":"1995","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1074\/jbc.M408438200","article-title":"Methionine Adenosyltransferase: Adrenergic-cAMP Mechanism Regulates a Daily Rhythm in Pineal Expression","volume":"280","author":"Kim","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0163-7258(96)00197-0","article-title":"S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications","volume":"73","author":"Mato","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nchembio.2384","article-title":"Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A","volume":"13","author":"Quinlan","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0168-9525(97)01013-5","article-title":"Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products","volume":"13","author":"Kotb","year":"1997","journal-title":"Trends Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.jhep.2013.04.031","article-title":"Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis","volume":"59","author":"Frau","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.mce.2009.07.010","article-title":"Pineal function: Impact of microarray analysis","volume":"314","author":"Klein","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.7150\/ijms.51743","article-title":"Identifying daily changes in circRNAs and circRNA-associated-ceRNA networks in the rat pineal gland","volume":"18","author":"Zheng","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1242\/jcs.065771","article-title":"Post-transcriptional control of circadian rhythms","volume":"124","author":"Kojima","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1038\/s41598-017-02152-x","article-title":"Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders","volume":"7","author":"Pagan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"bqab255","DOI":"10.1210\/endocr\/bqab255","article-title":"CircRNA-WNK2 Acts as a ceRNA for miR-328a-3p to Promote AANAT Expression in the Male Rat Pineal Gland","volume":"163","author":"Zheng","year":"2022","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25312","DOI":"10.1074\/jbc.M112.356733","article-title":"MicroRNAs in the Pineal Gland: miR-483 regulates melatonin synthesis by targeting arylalkylamine N-acetyltransferase","volume":"287","author":"Clokie","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1093\/nar\/gkt1359","article-title":"The light-induced transcriptome of the zebrafish pineal gland reveals complex regulation of the circadian clockwork by light","volume":"42","author":"Alon","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.4103\/1673-5374.308101","article-title":"The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage","volume":"16","author":"Sha","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2017.05.001","article-title":"Up-regulation of miR-325-3p suppresses pineal aralkylamine N-acetyltransferase (Aanat) after neonatal hypoxia\u2013ischemia brain injury in rats","volume":"1668","author":"Yang","year":"2017","journal-title":"Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1600-079X.2008.00627.x","article-title":"Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland","volume":"45","author":"Huang","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1210\/en.2015-1888","article-title":"Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland","volume":"157","author":"Rath","year":"2016","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1471-4159.2009.06457.x","article-title":"Modulation of Aanat gene transcription in the rat pineal gland","volume":"112","author":"Ho","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.mce.2006.03.022","article-title":"Timing of mitogen-activated protein kinase (MAPK) activation in the rat pineal gland","volume":"252","author":"Ho","year":"2006","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0021-9258(17)45266-5","article-title":"Control of Hydroxyindole O-Methyltransferase Activity in the Rat Pineal Gland by Environmental Lighting","volume":"240","author":"Axelrod","year":"1965","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/j.1471-4159.1980.tb03688.x","article-title":"Regulation of Rat Pineal Hydroxyindole-O-Methyltransferase: Evidence of S-Adenosylmethionine-Mediated Glucocorticoid Control","volume":"35","author":"Sandrock","year":"1980","journal-title":"J. Neurochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000125797","article-title":"Rhythmic Release Pattern of Pineal Melatonin in Rodents","volume":"53","author":"Chan","year":"1991","journal-title":"Neuroendocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e12552","DOI":"10.1111\/jpi.12552","article-title":"MicroRNA-7 inhibits melatonin synthesis by acting as a linking molecule between leptin and norepinephrine signaling pathways in pig pineal gland","volume":"66","author":"Qiu","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1080\/21655979.2020.1832343","article-title":"Circular RNA hsa_circ_0007364 increases cervical cancer progression through activating methionine adenosyltransferase II alpha (MAT2A) expression by restraining microRNA-101-5p","volume":"11","author":"Chen","year":"2020","journal-title":"Bioengineered"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5510869","DOI":"10.1155\/2021\/5510869","article-title":"Circ_0044516 Regulates miR-136\/MAT2A Pathway to Facilitate Lung Cancer Development","volume":"2021","author":"Chen","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_41","first-page":"12251","article-title":"Hsa_circ_0000337 promotes proliferation, migration and invasion in glioma by competitively binding miRNA-942-5p and thus upregulates MAT2A","volume":"24","author":"Liu","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1089\/dna.2020.6205","article-title":"MALAT1 Inhibits Proliferation of HPV16-Positive Cervical Cancer by Sponging miR-485-5p to Promote Expression of MAT2A","volume":"40","author":"Tie","year":"2021","journal-title":"DNA Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1210\/endo.137.7.8770929","article-title":"Melatonin synthesis: Analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland","volume":"137","author":"Roseboom","year":"1996","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jneumeth.2010.07.007","article-title":"A standardized surgical technique for rat superior cervical ganglionectomy","volume":"192","author":"Savastano","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e12643","DOI":"10.1111\/jpi.12643","article-title":"Melatonin protects the retina from experimental nonexudative age-related macular degeneration in mice","volume":"68","author":"Fleitas","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e12629","DOI":"10.1111\/jpi.12629","article-title":"Circadian regulation and molecular role of the Bsx homeobox gene in the adult pineal gland","volume":"68","author":"Carstensen","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1530\/JME-20-0036","article-title":"circAkap17b acts as a miR-7 family molecular sponge to regulate FSH secretion in rat pituitary cells","volume":"65","author":"Wang","year":"2020","journal-title":"J. Mol. Endocrinol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15477\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:35:36Z","timestamp":1760146536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,7]]},"references-count":47,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415477"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415477","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,7]]}}}