Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.
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.
Brasacchio
Daniella
D
Epigenetics in Human Health and Disease Laboratory, The Alfred Medical Research and Education Precinct, Baker IDI Heart and Diabetes Institute, Victoria, Australia.
Okabe
Jun
J
Tikellis
Christos
C
Balcerczyk
Aneta
A
George
Prince
P
Baker
Emma K
EK
Calkin
Anna C
AC
Brownlee
Michael
M
Cooper
Mark E
ME
El-Osta
Assam
A
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
D017931:DNA Primers; D018076:DNA, Complementary; D012313:RNA; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine