title: Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.
abstract: OBJECTIVE
  Results from the Diabetes Control Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate >5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as "hyperglycemic memory." We have hypothesized that transient hyperglycemia mediates persistent gene-activating events attributed to changes in epigenetic information.
  
  
  METHODS
  Models of transient hyperglycemia were used to link NFkappaB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFkappaB-p65 chromatin.
  
  
  RESULTS
  The sustained upregulation of the NFkappaB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia.
  
  
  CONCLUSIONS
  These studies indicate that the active transcriptional state of the NFkappaB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes.
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, The Alfred Medical Research and Education Precinct, Baker IDI Heart and Diabetes Institute, Victoria, Australia.
authors.forename: Daniella
authors.initials: D
authors.lastname: Brasacchio
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.forename: Christos
authors.initials: C
authors.lastname: Tikellis
authors.forename: Aneta
authors.initials: A
authors.lastname: Balcerczyk
authors.forename: Prince
authors.initials: P
authors.lastname: George
authors.forename: Emma K
authors.initials: EK
authors.lastname: Baker
authors.forename: Anna C
authors.initials: AC
authors.lastname: Calkin
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000818:Animals; D002417:Cattle; D019175:DNA Methylation; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D003925:Diabetic Angiopathies / Q000235:genetics; D004730:Endothelium, Vascular / Q000502:physiology; D020022:Genetic Predisposition to Disease; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D012313:RNA; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine