Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail

Daniella Brasacchio, Jun Okabe, Christos Tikellis, Aneta Balcerczyk, Prince George, Emma K. Baker, Anna C. Calkin, Michael Brownlee, Mark E. Cooper, Assam El-Osta

Research output: Contribution to journalArticleResearchpeer-review

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. RESEARCH DESIGN AND METHODS-Models of transient hyperglycemia were used to link NFxB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyl- transferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. RESULTS-The sustained upregulation of the NFκB-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 NFxB-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.

Original languageEnglish
Pages (from-to)1229-1236
Number of pages8
JournalDiabetes
Volume58
Issue number5
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Cite this

@article{1a71a032fdb245459d4d320d358a2bff,
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. RESEARCH DESIGN AND METHODS-Models of transient hyperglycemia were used to link NFxB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyl- transferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. RESULTS-The sustained upregulation of the NFκB-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 NFxB-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.",
author = "Daniella Brasacchio and Jun Okabe and Christos Tikellis and Aneta Balcerczyk and Prince George and Baker, {Emma K.} and Calkin, {Anna C.} and Michael Brownlee and Cooper, {Mark E.} and Assam El-Osta",
year = "2009",
month = "5",
doi = "10.2337/db08-1666",
language = "English",
volume = "58",
pages = "1229--1236",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "5",

}

Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. / Brasacchio, Daniella; Okabe, Jun; Tikellis, Christos; Balcerczyk, Aneta; George, Prince; Baker, Emma K.; Calkin, Anna C.; Brownlee, Michael; Cooper, Mark E.; El-Osta, Assam.

In: Diabetes, Vol. 58, No. 5, 05.2009, p. 1229-1236.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail

AU - Brasacchio, Daniella

AU - Okabe, Jun

AU - Tikellis, Christos

AU - Balcerczyk, Aneta

AU - George, Prince

AU - Baker, Emma K.

AU - Calkin, Anna C.

AU - Brownlee, Michael

AU - Cooper, Mark E.

AU - El-Osta, Assam

PY - 2009/5

Y1 - 2009/5

N2 - 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. RESEARCH DESIGN AND METHODS-Models of transient hyperglycemia were used to link NFxB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyl- transferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. RESULTS-The sustained upregulation of the NFκB-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 NFxB-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.

AB - 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. RESEARCH DESIGN AND METHODS-Models of transient hyperglycemia were used to link NFxB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyl- transferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. RESULTS-The sustained upregulation of the NFκB-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 NFxB-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.

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DO - 10.2337/db08-1666

M3 - Article

VL - 58

SP - 1229

EP - 1236

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 5

ER -