{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:39:56Z","timestamp":1791171596544,"version":"4.1.0"},"reference-count":47,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,1]]},"abstract":"<jats:p>Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitary-adrenal axis activity following ELS exposure in male mice. Here, ELS comprising daily separation of pups from their dams on postnatal days 1\u201310 was observed to up-regulate the expression of the pituitary proopiomelanocortin (Pomc) gene; POMC serves as a prohormone for ACTH, a key mediator of the adrenocortical response to stress. Detailed analysis revealed that the increase in Pomc mRNA levels results from a reduction in DNA methylation at a critical regulatory region of the Pomc gene; interestingly, this change occurs with some delay after ELS and persists for up to 1 year. Using a Pomc-expressing pituitary cell line (AtT20), we confirmed a role for DNA methylation in restraining Pomc expression under resting conditions: specifically, we show that CpG site-specific methylation of the Pomc promoter represses Pomc mRNA transcription. Further, we show high-affinity binding of methyl-CpG binding protein-2 to the distal promoter of Pomc, suggesting that methyl-CpG binding protein-2 acts in association with the chromatin modifiers histone deacetylase 2 and DNA methyltransferase 1 to repress Pomc gene expression. Collectively, these experiments contribute to our understanding of the mechanisms through which environmental cues are translated into stable changes (\u201ccellular memory\u201d) in neuroendocrine cells.<\/jats:p>","DOI":"10.1210\/en.2013-1868","type":"journal-article","created":{"date-parts":[[2014,2,7]],"date-time":"2014-02-07T17:59:09Z","timestamp":1391795949000},"page":"1751-1762","source":"Crossref","is-referenced-by-count":129,"title":["Early-Life Stress Reduces DNA Methylation of the Pomc Gene in Male Mice"],"prefix":"10.1210","volume":"155","author":[{"given":"Yonghe","family":"Wu","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre V.","family":"Patchev","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Daniel","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osborne F.X.","family":"Almeida","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Spengler","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071612064081300_B1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.psyneuen.2005.03.013","article-title":"Developmental determinants of sensitivity and resistance to stress","volume":"30","author":"Levine","year":"2005","journal-title":"Psychoneuroendocrinology"},{"key":"2020071612064081300_B2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrn1683","article-title":"Stress and the brain: from adaptation to disease","volume":"6","author":"de Kloet","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"2020071612064081300_B3","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/S0006-3223(01)01157-X","article-title":"The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies","volume":"49","author":"Heim","year":"2001","journal-title":"Biol Psychiatry"},{"key":"2020071612064081300_B4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of in utero and early-life conditions on adult health and disease","volume":"359","author":"Gluckman","year":"2008","journal-title":"N Engl J Med"},{"key":"2020071612064081300_B5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00213-010-1916-6","article-title":"The role of early life stress as a predictor for alcohol and drug dependence","volume":"214","author":"Enoch","year":"2011","journal-title":"Psychopharmacology (Berl)"},{"key":"2020071612064081300_B6","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.psyneuen.2006.12.013","article-title":"Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats","volume":"32","author":"Aisa","year":"2007","journal-title":"Psychoneuroendocrinology"},{"key":"2020071612064081300_B7","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.psyneuen.2008.03.008","article-title":"The link between childhood trauma and depression: insights from HPA axis studies in humans","volume":"33","author":"Heim","year":"2008","journal-title":"Psychoneuroendocrinology"},{"key":"2020071612064081300_B8","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0893-133X(00)00159-7","article-title":"The corticosteroid receptor hypothesis of depression","volume":"23","author":"Holsboer","year":"2000","journal-title":"Neuropsychopharmacology"},{"key":"2020071612064081300_B9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nrn2132","article-title":"Epigenetic regulation in psychiatric disorders","volume":"8","author":"Tsankova","year":"2007","journal-title":"Nat Rev Neurosci"},{"key":"2020071612064081300_B10","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nn.2270","article-title":"Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse","volume":"12","author":"McGowan","year":"2009","journal-title":"Nat Neurosci"},{"key":"2020071612064081300_B11","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature05919","article-title":"Phenotypic plasticity and the epigenetics of human disease","volume":"447","author":"Feinberg","year":"2007","journal-title":"Nature"},{"key":"2020071612064081300_B12","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng1089","article-title":"Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals","volume":"33","author":"Jaenisch","year":"2003","journal-title":"Nat Genet"},{"key":"2020071612064081300_B13","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/nn1276","article-title":"Epigenetic programming by maternal behavior","volume":"7","author":"Weaver","year":"2004","journal-title":"Nat Neurosci"},{"key":"2020071612064081300_B14","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1038\/nn.2436","article-title":"Dynamic DNA methylation programs persistent adverse effects of early-life stress","volume":"12","author":"Murgatroyd","year":"2009","journal-title":"Nat Neurosci"},{"key":"2020071612064081300_B15","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1210\/en.2005-1119","article-title":"Maternal care associated with methylation of the estrogen receptor-\u03b11b promoter and estrogen receptor-\u03b1 expression in the medial preoptic area of female offspring","volume":"147","author":"Champagne","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612064081300_B16","doi-asserted-by":"crossref","first-page":"e1002543","DOI":"10.1371\/journal.pgen.1002543","article-title":"An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity","volume":"8","author":"Kuehnen","year":"2012","journal-title":"PLoS Genet"},{"key":"2020071612064081300_B17","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1017\/S0007114511000973","article-title":"Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene","volume":"106","author":"Palou","year":"2011","journal-title":"Br J Nutr"},{"key":"2020071612064081300_B18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00702-010-0378-7","article-title":"DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence","volume":"117","author":"Muschler","year":"2010","journal-title":"J Neural Transm"},{"key":"2020071612064081300_B19","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1210\/en.2010-0094","article-title":"Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition","volume":"151","author":"Stevens","year":"2010","journal-title":"Endocrinology"},{"key":"2020071612064081300_B20","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.biopsych.2012.04.006","article-title":"Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations","volume":"72","author":"Govorko","year":"2012","journal-title":"Biol Psychiatry"},{"key":"2020071612064081300_B21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/S0018-506X(03)00063-1","article-title":"Anxiety and fear behaviors in adult male and female C57BL\/6 mice are modulated by maternal separation","volume":"43","author":"Romeo","year":"2003","journal-title":"Horm Behav"},{"key":"2020071612064081300_B22","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1176\/appi.ajp.159.8.1265","article-title":"Parental depression: animal models of an adverse life event","volume":"159","author":"Newport","year":"2002","journal-title":"Am J Psychiatry"},{"key":"2020071612064081300_B23","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4161\/epi.1.3.3327","article-title":"Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector","volume":"1","author":"Klug","year":"2006","journal-title":"Epigenetics"},{"key":"2020071612064081300_B24","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1128\/MCB.23.3.988-1003.2003","article-title":"Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding","volume":"23","author":"Hoffmann","year":"2003","journal-title":"Mol Cell Biol"},{"key":"2020071612064081300_B25","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.molcel.2005.07.021","article-title":"DNA binding selectivity of MeCP2 due to a requirement for A\/T sequences adjacent to methyl-CpG","volume":"19","author":"Klose","year":"2005","journal-title":"Mol Cell"},{"key":"2020071612064081300_B26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1677\/jme.0.0120365","article-title":"Transcripts and CpG islands associated with the pro-opiomelanocortin gene and other neurally expressed genes","volume":"12","author":"Gardiner-Garden","year":"1994","journal-title":"J Mol Endocrinol"},{"key":"2020071612064081300_B27","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1210\/mend.16.7.0863","article-title":"Activation and induction of NUR77\/NURR1 in corticotrophs by CRH\/cAMP: involvement of calcium, protein kinase A, and MAPK pathways","volume":"16","author":"Kovalovsky","year":"2002","journal-title":"Mol Endocrinol"},{"key":"2020071612064081300_B28","doi-asserted-by":"crossref","first-page":"6673","DOI":"10.1128\/MCB.17.11.6673","article-title":"NeuroD1\/beta2 contributes to cell-specific transcription of the proopiomelanocortin gene","volume":"17","author":"Poulin","year":"1997","journal-title":"Mol Cell Biol"},{"key":"2020071612064081300_B29","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1210\/me.2007-0567","article-title":"Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin","volume":"22","author":"Lavoie","year":"2008","journal-title":"Mol Endocrinol"},{"key":"2020071612064081300_B30","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1101\/gad.1444606","article-title":"Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease","volume":"20","author":"Bilodeau","year":"2006","journal-title":"Genes Dev"},{"key":"2020071612064081300_B31","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1074\/jbc.M210256200","article-title":"The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation","volume":"278","author":"Fuks","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071612064081300_B32","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome","volume":"27","author":"Guy","year":"2001","journal-title":"Nat Genet"},{"key":"2020071612064081300_B33","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/77124","article-title":"DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters","volume":"25","author":"Robertson","year":"2000","journal-title":"Nat Genet"},{"key":"2020071612064081300_B34","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/BF01953202","article-title":"Cell size and cell division of the anterior pituitary: time course in the growing rat","volume":"35","author":"Friend","year":"1979","journal-title":"Experientia"},{"key":"2020071612064081300_B35","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1046\/j.1365-2826.1998.00191.x","article-title":"Anterior pituitary cell population control: basal cell turnover and the effects of adrenalectomy and dexamethasone treatment","volume":"10","author":"Nolan","year":"1998","journal-title":"J Neuroendocrinol"},{"key":"2020071612064081300_B36","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1677\/joe.0.1770365","article-title":"Proopiomelanocortin gene expression and DNA methylation: implications for Cushing's syndrome and beyond","volume":"177","author":"Newell-Price","year":"2003","journal-title":"J Endocrinol"},{"key":"2020071612064081300_B37","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1210\/mend.15.2.0599","article-title":"The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression","volume":"15","author":"Newell-Price","year":"2001","journal-title":"Mol Endocrinol"},{"key":"2020071612064081300_B38","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.tig.2007.05.008","article-title":"Epigenetics and aging: the targets and the marks","volume":"23","author":"Fraga","year":"2007","journal-title":"Trends Genet"},{"key":"2020071612064081300_B39","doi-asserted-by":"crossref","first-page":"9948","DOI":"10.1016\/S0021-9258(18)61057-9","article-title":"Genomic 5-methyldeoxycytidine decreases with age","volume":"262","author":"Wilson","year":"1987","journal-title":"J Biol Chem"},{"key":"2020071612064081300_B40","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1046\/j.1529-8817.2004.00081.x","article-title":"Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study","volume":"68","author":"Fuke","year":"2004","journal-title":"Ann Hum Genet"},{"key":"2020071612064081300_B41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1152\/physiolgenomics.00146.2009","article-title":"Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences","volume":"41","author":"Jintaridth","journal-title":"Physiol Genomics"},{"key":"2020071612064081300_B42","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1210\/endo-123-1-340","article-title":"Age-related changes in proopiomelanocortin messenger ribonucleic acid levels in hypothalamus and pituitary of female C57BL\/6J mice","volume":"123","author":"Nelson","year":"1988","journal-title":"Endocrinology"},{"key":"2020071612064081300_B43","doi-asserted-by":"crossref","first-page":"18267","DOI":"10.1073\/pnas.0608702103","article-title":"Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome","volume":"103","author":"McGill","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612064081300_B44","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1093\/hmg\/ddi229","article-title":"Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome","volume":"14","author":"Nuber","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020071612064081300_B45","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/ng1516","article-title":"Brahma links the SWI\/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing","volume":"37","author":"Harikrishnan","year":"2005","journal-title":"Nat Genet"},{"key":"2020071612064081300_B46","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1083\/jcb.43.3.626","article-title":"DNA synthesis in the rat anterior pituitary: an electron microscope radioautographic study","volume":"43","author":"Mastro","year":"1969","journal-title":"J Cell Biol"},{"key":"2020071612064081300_B47","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1074\/jbc.M209923200","article-title":"Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1","volume":"278","author":"Kimura","year":"2003","journal-title":"J Biol Chem"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/5\/1751\/10825695\/endo1751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/5\/1751\/10825695\/endo1751.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,26]],"date-time":"2022-03-26T00:59:58Z","timestamp":1648256398000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/155\/5\/1751\/2423322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5,1]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2013-1868","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5,1]]}}}