title: Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes.
abstract: To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, Scania University Hospital, Malmö, Sweden.
authors.forename: Marloes Dekker
authors.initials: MD
authors.lastname: Nitert
authors.forename: Tasnim
authors.initials: T
authors.lastname: Dayeh
authors.forename: Peter
authors.initials: P
authors.lastname: Volkov
authors.forename: Targ
authors.initials: T
authors.lastname: Elgzyri
authors.forename: Elin
authors.initials: E
authors.lastname: Hall
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.forename: Beatrice T
authors.initials: BT
authors.lastname: Yang
authors.forename: Stefan
authors.initials: S
authors.lastname: Lang
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Ylva
authors.initials: Y
authors.lastname: Wessman
authors.forename: Holger
authors.initials: H
authors.lastname: Weishaupt
authors.forename: Joanne
authors.initials: J
authors.lastname: Attema
authors.forename: Mia
authors.initials: M
authors.lastname: Abels
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Per-Anders
authors.initials: PA
authors.lastname: Jansson
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.forename: Karl-Fredrik
authors.initials: KF
authors.lastname: Eriksson
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015444:Exercise / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D026161:MADS Domain Proteins / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D054419:Receptors, Adiponectin / Q000235:genetics
chemical_list: C475418:ADIPOR1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D047908:Intracellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D009363:Neoplasm Proteins; C493728:RUNX1 protein, human; D054419:Receptors, Adiponectin; C477698:THADA protein, human; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases