ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity
ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity
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Publication Date:
26 April 2017
Lillycrop K, Murray R, Cheong C, Teh AL, Clarke-Harris R, Barton S, Costello P, Garratt E, Cook E, Titcombe P, Shunmuganathan B, Liew SJ, Chua YC, Lin X, Wu Y, Burdge GC, Cooper C, Inskip HM, Karnani N, Hopkins JC, Childs CE, Chavez CP, Calder PC, Yap F, Lee YS, Chong YS, Melton PE, Beilin L, Huang RC, Gluckman PD, Harvey N, Hanson MA, Holbrook JD; EpiGen Consortium, Godfrey KM. “ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity”. EBioMedicine. 2017 May;19:60-72. doi: 10.1016/j.ebiom.2017.03.037.
Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.
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This work was supported by funding from the Medical Research Council ( MC_UU_12011/4 , MC_U147585827 and MC_ST_U12055 ) British Heart Foundation ( RG/15/17/3174 and RG/07/009 ), Nestec ( BIDG/2013/00456 ), NIHR Musculoskeletal Biomedical Research Unit, University of Oxford , NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust , the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme administered by the Singapore Ministry of Health's National Medical Research Council (NMRC) ( NMRC/TCN/012-NUHS/2014 ), Singapore- NMRC/TCR/004-NUS/2008 ; NMRC/TCR/012-NUHS/2014 . The BIOCLAIMS study was supported by the European Commission Seventh Framework Programme (Grant agreement no. 244995 ). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore. KMG is supported by the European Union Seventh Framework Programme ( FP7/2007-2013 ), project EarlyNutrition under grant agreement no. 289346. The RAINE study was supported by The Australian National Health and Medical Research Council (NHMRC) ( 1059711 ).
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