TY - JOUR
T1 - Transcriptional profiling at the DLK1/MEG3 domain explains clinical overlap between imprinting disorders
AU - Habib, Walid Abi
AU - Brioude, Frédéric
AU - Azzi, Salah
AU - Rossignol, Sylvie
AU - Linglart, Agnès
AU - Sobrier, Marie Laure
AU - Giabicani, Éloïse
AU - Steunou, Virginie
AU - Harbison, Madeleine D.
AU - Le Bouc, Yves
AU - Netchine, Irène
N1 - Funding Information:
We thank the patients, their families and their physicians, J. Salem, D. Carney, the MAGIC Foundation, and also the “Association Françaises des Familles ayant un enfant atteint du Syndrome Silver Russell ou né Petit pour l’Age Gestationnel (AFIF/PAG)” for support. We thank S. Chantot-Bastaraud (INSERM U933) for performing the SNP array analyses and the primary fibroblast cultures for the TS14 patients and L. Perin for performing DLK1 ELISA. We would also like to thank N. Thibaud, C. Das Neves, M. le Jule, and E. Tagodoe (the diagnostic technicians of the Pediatric Endocrinology Department, Trousseau Pediatric Hospital). Funding: This work was supported by the INSERM, funding from the Université Pierre et Marie Curie (UPMC-Paris6), the Agence Nationale de la Recherche (ANR EPIFEGRO 2010). W.A.H. was supported by the People Programme Marie Curie Actions (MCA) of the European Union’s Seventh Framework Programme FP7/ITN Ingenium 2007–2013 under REA grant agreement no. 290123 and by the Société Française d’Endocrinologie et Diabétologie Pédiatrique through a Lilly grant. F.B. was supported by a Novo Nordisk Growth Hormone, Growth and Metabolism grant. W.A.H., I.N., and Y.L.B. are members of the European Union’s Seventh Framework Programme FP7/ITN Ingenium 2007–2013. F.B., A.L., and I.N. are members of the EUCID.net network COST (BM1208).
Publisher Copyright:
Copyright © 2019 The Authors.
PY - 2019/2/20
Y1 - 2019/2/20
N2 - Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its DLK1/ MEG3 domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to IGF2 down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers IGF2 levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
AB - Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its DLK1/ MEG3 domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to IGF2 down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers IGF2 levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
UR - http://www.scopus.com/inward/record.url?scp=85062058122&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aau9425
DO - 10.1126/sciadv.aau9425
M3 - Article
C2 - 30801013
AN - SCOPUS:85062058122
SN - 2375-2548
VL - 5
JO - Science advances
JF - Science advances
IS - 2
M1 - eaau9425
ER -