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Epigenetic and Metabolism: Glucose and Homeotic Transcription Factor PREP1 VRP Suggested Epigenetics and Metabolism

  • Luigi Albano
  • Paolo Emidio Macchia
  • Paola UngaroEmail author
Reference work entry

Abstract

Based on current knowledge, it is evident that epigenetic mechanisms contribute to the pathogenesis of type 2 diabetes and its complications. Transient hyperglycemia induces recruitment of the SET7 methyltransferase and H3K4 monomethylation in the promoter of the NF-κB subunit p65 and subsequent expression of NF-κB-dependent genes involved in the progression of diabetic complications.

PREP1 is a gene having a role in insulin sensitivity of glucose transport, as its overexpression causes insulin resistance. In vitro and in vivo exposure to high glucose concentrations increased PREP1 expression levels. This event was preceded by recruitment of NF-κB p65 at the SET7 5′-flanking region, along with recruitment of the SET7 histone methyltransferase and p300 histone acetyltransferase to the same regulatory region. Indeed, high glucose exposure was associated with increased histone H3 Lys4 mono- and dimethylation and Lys9/14 acetylation at the PREP1 promoter. NF-κB recruitment is fundamental in driving the action of epigenetic enzymes at the PREP1 5′ regulatory region, since different NF-κB pharmacologic inhibitors attenuated t3hese effects.

The consequence of PREP1 overexpression is the recruitment of the repressor complex myocyte enhancer factor 2 (MEF2)/histone deacetylase 5 (HDAC5) at the GLUT4 promoter that leads to reduction of its expression. Thus, PREP1 can be considered as a target downstream of NF-κB that is capable to induce insulin resistance in response to hyperglycemia and inflammatory hits. Histone modifications at the PREP1 gene may be responsible for insulin resistance in individuals with type 2 diabetes.

Keywords

Type 2 diabetes Histone modification enzymes NF-κB PREP1 GLUT4 Chromatin remodeling Hyperglycemia Metabolic memory HDAC5 MEF2 

List of Abbreviations

(p)AMPK

(Phosphorylated)5′AMP-activated protein kinase

AcH3

Histone H3 acetylation

AGEs

Advanced glycation end products

ChIP

Chromatin immunoprecipitation

GLUT4

Glucose transporter type 4

H3K4me1

Histone H3 Lys4 monomethylation

H3K4me2

Histone H3 Lys4 dimethylation

HDAC5

Histone deacetylase 5

HG

High glucose

HMOX1

Heme oxygenase 1

MCP1

Monocyte chemoattractant protein-1

MEF2

Myocyte enhancer factor 2

NF-κB

Nuclear factor κ light chain enhancer of activated B cells

NG

Normal glucose

PREP1

Pbx-regulating protein 1

ROS

Reactive oxygen species

SET7/9

Su(var)3-9, enhancer-of-zeste, trithorax domain-containing lysine methyltransferase 7

STZ

Streptozotocin

T2DM

Type 2 diabetes mellitus

TALE

Three-amino acid loop extension

VCAM1

Vascular cell adhesion molecule 1

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Luigi Albano
    • 1
  • Paolo Emidio Macchia
    • 2
  • Paola Ungaro
    • 3
    Email author
  1. 1.Department of Translational Medical SciencesUniversity of Naples “Federico II”NaplesItaly
  2. 2.Department of Clinical Medicine and SurgeryUniversity of Naples “Federico II”NaplesItaly
  3. 3.Institute for Experimental Endocrinology and Oncology“G. Salvatore”(IEOS), National Research Council (CNR)NaplesItaly

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