PUBLICATION

Epigenetic Studies Point to DNA Replication/Repair Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes

Authors

Leontovich, A.A., Intine, R.V., Sarras, M.P.

ID

ZDB-PUB-160317-6

Date

2016

Source

Journal of Diabetes Research 2016: 2860780 (Journal)

Registered Authors

Sarras, Michael P., Jr.

Keywords

none

MeSH Terms

DNA Repair/genetics*
Animals
Diabetes Complications/genetics*
Diabetes Complications/metabolism
Gene Regulatory Networks
Diabetes Mellitus, Experimental/blood
Diabetes Mellitus, Experimental/complications*
Zebrafish
Animal Fins/metabolism
Epigenesis, Genetic*
DNA Repair Enzymes/genetics*
Phenotype
DNA Replication/genetics*
Heredity*
Blood Glucose/metabolism
DNA Methylation
Disease Models, Animal
Oligonucleotide Array Sequence Analysis
Gene Expression Profiling/methods
Computational Biology
Genetic Predisposition to Disease
Energy Metabolism/genetics*

(all 22)

PubMed

26981540 Full text @ J. Diabetes Res.

Abstract

Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques. Bioinformatics analysis of the data found that genes of the DNA replication/DNA metabolism process group (with upregulation of the apex1, mcm2, mcm4, orc3, lig1, and dnmt1 genes) were altered in the DM state and these molecular changes continued into MM. Interestingly, DNA methylation changes could be found as far as 6-13 kb upstream of the transcription start site for these genes suggesting potential higher levels of epigenetic control. In conclusion, DNA methylation changes in members of the DNA replication/repair process group best explain the heritable nature of cell proliferation impairment found in the zebrafish DM/MM model. These results are consistent with human diabetic epigenetic studies and provide one explanation for the persistence of long term tissue complications as seen in diabetes.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
apex1	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
dnmt1	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
lig1	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
mcm2	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
mcm4	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
orc3	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3
pola2	WT	chemical treatment: streptozocin	Adult	caudal fin	RTPCR	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: streptozocin	Adult	caudal fin apex1 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin dnmt1 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin lig1 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin mcm2 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin mcm4 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin orc3 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	caudal fin pola2 expression increased amount, abnormal	Fig. 3
WT	chemical treatment: streptozocin	Adult	DNA-methyltransferase activity process quality, abnormal	Fig. 6
WT	chemical treatment: streptozocin	Adult	DNA-methyltransferase activity process quality, abnormal	Fig. 7
WT	chemical treatment: streptozocin	Adult	DNA-methyltransferase activity process quality, abnormal	Fig. 4

1 - 10 of 11

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Mutations / Transgenics

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
diabetes mellitus	WT	chemical treatment: streptozocin	TAS

Sequence Targeting Reagents

Fish

Fish
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Leontovich et al., 2016 ZDB-PUB-160317-6 PMID:26981540

Epigenetic Studies Point to DNA Replication/Repair Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes

Leontovich et al., 2016

ZDB-PUB-160317-6
PMID:26981540