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Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy.

Abstract Diabetes elevates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 damages mitochondria, accelerating retinal capillary cell apoptosis, a phenomenon which precedes the development of retinopathy. Diabetes also favors epigenetic modifications regulating the expression of many genes. DNA methylation is maintained by methylating-hydroxymethylating enzymes, and retinal DNA methyltransferase (Dnmt) is activated in diabetes. Our aim is to investigate the role of DNA methylation in MMP-9 regulation. The effect of high glucose on 5-methylcytosine (5mC) and 5-hydroxymethyl cytosine (5hmC), and binding of Dnmt1 and hydroxymethylating enzyme (Tet2) on MMP-9 promoter were quantified in retinal endothelial cells. Specific role of Tet2 in MMP-9 activation was validated using Tet2-siRNA. The results were confirmed in the retina from streptozotocin-induced diabetic mouse. Although glucose increased Dnmt1 binding at MMP-9 promoter, it decreased 5mC levels. At the same promoter site, Tet2 binding and 5hmC levels were elevated. Tet2-siRNA ameliorated increase in 5hmC and MMP-9 transcription, and protected mitochondrial damage. Diabetic mice also presented similar dynamic DNA methylation changes in the retinal MMP-9 promoter. Thus, in diabetes transcription of retinal MMP-9 is maintained, in part, by an active DNA methylation-hydroxymethylation process, and regulation of this machinery should help maintain mitochondrial homeostasis and inhibit the development/progression of diabetic retinopathy.
PMID
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Molecular Mechanism of Transcriptional Regulation of Matrix Metalloproteinase-9 in Diabetic Retinopathy.

Authors

Mayor MeshTerms

DNA Methylation

Keywords
Journal Title laboratory investigation; a journal of technical methods and pathology
Publication Year Start




PMID- 27454437
OWN - NLM
STAT- MEDLINE
DA  - 20160923
DCOM- 20170612
LR  - 20170612
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Linking)
VI  - 96
IP  - 10
DP  - 2016 Oct
TI  - Dynamic DNA methylation of matrix metalloproteinase-9 in the development of
      diabetic retinopathy.
PG  - 1040-9
LID - 10.1038/labinvest.2016.78 [doi]
AB  - Diabetes elevates matrix metalloproteinase-9 (MMP-9) in the retina and its
      capillary cells, and activated MMP-9 damages mitochondria, accelerating retinal
      capillary cell apoptosis, a phenomenon which precedes the development of
      retinopathy. Diabetes also favors epigenetic modifications regulating the
      expression of many genes. DNA methylation is maintained by
      methylating-hydroxymethylating enzymes, and retinal DNA methyltransferase (Dnmt) 
      is activated in diabetes. Our aim is to investigate the role of DNA methylation
      in MMP-9 regulation. The effect of high glucose on 5-methylcytosine (5mC) and
      5-hydroxymethyl cytosine (5hmC), and binding of Dnmt1 and hydroxymethylating
      enzyme (Tet2) on MMP-9 promoter were quantified in retinal endothelial cells.
      Specific role of Tet2 in MMP-9 activation was validated using Tet2-siRNA. The
      results were confirmed in the retina from streptozotocin-induced diabetic mouse. 
      Although glucose increased Dnmt1 binding at MMP-9 promoter, it decreased 5mC
      levels. At the same promoter site, Tet2 binding and 5hmC levels were elevated.
      Tet2-siRNA ameliorated increase in 5hmC and MMP-9 transcription, and protected
      mitochondrial damage. Diabetic mice also presented similar dynamic DNA
      methylation changes in the retinal MMP-9 promoter. Thus, in diabetes
      transcription of retinal MMP-9 is maintained, in part, by an active DNA
      methylation-hydroxymethylation process, and regulation of this machinery should
      help maintain mitochondrial homeostasis and inhibit the development/progression
      of diabetic retinopathy.
FAU - Kowluru, Renu A
AU  - Kowluru RA
AD  - Department of Ophthalmology, Kresge Eye Institute, Wayne State University,
      Detroit, MI, USA.
FAU - Shan, Yang
AU  - Shan Y
AD  - Department of Ophthalmology, Kresge Eye Institute, Wayne State University,
      Detroit, MI, USA.
FAU - Mishra, Manish
AU  - Mishra M
AD  - Department of Ophthalmology, Kresge Eye Institute, Wayne State University,
      Detroit, MI, USA.
LA  - eng
GR  - R01 EY014370/EY/NEI NIH HHS/United States
GR  - R01 EY017313/EY/NEI NIH HHS/United States
GR  - R01 EY022230/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20160725
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (RNA, Small Interfering)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - *DNA Methylation
MH  - Diabetes Mellitus, Experimental/complications
MH  - Diabetic Retinopathy/*enzymology/etiology
MH  - Endothelial Cells/enzymology
MH  - Matrix Metalloproteinase 9/*metabolism
MH  - Mice, Inbred C57BL
MH  - RNA, Small Interfering
MH  - Random Allocation
MH  - Retina/enzymology
PMC - PMC5035192
MID - NIHMS797282
OID - NLM: NIHMS797282 [Available on 01/25/17]
OID - NLM: PMC5035192 [Available on 01/25/17]
COI - The authors declare no conflict of interest.
EDAT- 2016/07/28 06:00
MHDA- 2017/06/13 06:00
CRDT- 2016/07/26 06:00
PHST- 2016/04/22 [received]
PHST- 2016/06/13 [revised]
PHST- 2016/06/19 [accepted]
AID - labinvest201678 [pii]
AID - 10.1038/labinvest.2016.78 [doi]
PST - ppublish
SO  - Lab Invest. 2016 Oct;96(10):1040-9. doi: 10.1038/labinvest.2016.78. Epub 2016 Jul
      25.