EPIGENETIC ALTERATIONS IN PATIENTS
WITH TYPE 2 DIABETES MELLITUS
Karachanak-Yankova S1,a, Dimova R2,a, Nikolova D1, Nesheva D1, Koprinarova M3,
Maslyankov S4, Tafradjiska R5, Gateva P6, Velizarova M7, Hammoudeh Z1, Stoynev N2,
Toncheva D1, Tankova T2, Dimova I1,*
*Corresponding Author: Ivanka Dimova, Associate Professor, Department of Medical Genetics, Medical University
Sofia, Zdrave str. 2, 1431 Sofia, Bulgaria. Tel: +359-2-91-72-735. E-mail: ivanka.i.dimova@ gmail.com
page: 15
|
|
DISCUSSION
human
genome is affected by external environmental
factors, pathological conditions, as well as during the
normal processes of aging. Type 2 diabetes mellitus
is a common disease, the pathogenesis of which involves
factors such as genetic susceptibility, obesity,
decreased physical activity, imbalanced nutrition and
age. Age is an important factor that increases the
risk of T2DM and furthermore, increasing age and
T2DM both lead to decreased oxidation capacity and
mitochondrial dysfunction. The mechanisms of these
processes can be influenced by both genetic factors
and by epigenetic processes. Literature data suggest
that aging of the individual changes the epigenetic
status of the respiratory chain genes [1,5,6,13].
Methylation of CpG dinucleotides is an important
epigenetic mechanism used by vertebrate cells
to repress transcription of many tissue-specific genes
[14]. DNA methylation is the major modification of
eukaryotic genomes and plays an essential function
in mammalian progression. Methyl-CpG binding
domain proteins are capable of binding specifically
to methylated DNA and MBD1 and MBD2 can in
addition repress transcription from methylated gene
promoters [15]. In light of the functional significance
of MBD proteins in the epigenomic landscape, we
aimed to provide knowledge about the expression
of the MBD2 gene in blood samples of patients with
T2DM and hence to test it as a distinct epigenetic
biomarker for disease development. In the present study, we detected a 10.4-times average
increase in mRNA expression levels of MBD2
in patients with T2DM compared to controls. When
patients were stratified according to the duration
of the disease, this increase was highest in patients
with newly-diagnosed treatment naïve diabetes and
it decreased with the increase in the duration of the
disease still keeping the overexpressed levels. These
findings are in accordance with previous data pointing
out that high glucose levels induce DNA methylation
by up-regulating DNMT3a and MBD2 [16]. A probable
explanation for the decrease in MBD2 expression
in T2DM with a duration of more than 5 years
was the improved glycemic control of the treated
patients. Nevertheless, the expression was still high
when compared to the controls, indicating continuing
dysregulation of methylation processes as a result of
the disease, despite treatment.
The present study also involved analysis of the
methyl-ation status of 22 genes, connected to cellular
stress and toxicity, in four DNA pools of patients
with newly-diagnosed T2DM, patients with T2DM
duration of less or more than 5 years and in healthy
controls. Eleven of these genes were successfully
analyzed in all DNA pools. We were able to evaluate
the average methylated fraction for every gene
in each DNA pool. Notably, most of the analyzed
genes lacked methylated fractions in healthy individuals,
thus indicating an active transcriptional state.
The only exception was GDF15, which was almost
totally methylated in healthy controls. It is an extracellular
secretory protein, which is expressed at
high levels in placenta during development. Its role
in the early stages of endochondrial bone formation,
hematopoietic develop-ment, embryonic implantation
and placental function has been reported. Obviously,
the gene expression is silenced during adult
life by DNA methylation. In our patients, however,
this methylation was slightly decreased, indicating
some transcriptional activation. Recently, GDF15 was identified as one of the important plasma markers
that correlates with the cardiometabolic syndrome
[17]. Higher levels of GDF15 are associated with increased
cardiovascular and non cardiovascular mortality
as it plays a pivotal role in the development and
progression of cardiovascular diseases such as heart
failure, coronary artery disease, atrial fibrillation,
diabetes, cancer and cognitive impairment [18,19].
The decreasing methylation of GDF15 in the course
of T2DM is in line with the cardiovascular complications
of the disease.
Five genes: BRCA1, CCND1, Prdx2, SCARA3
and Tp53, showed consistent increase in DNA methylated
fraction in the course of T2DM. The methylated
fraction of the BRCA1 gene is increased over
40-times in T2DM. BRCA1 is a tumor suppressor
gene and its protein product is part of a complex
involved in the repair of DNA double-strand breaks.
This DNA reparation is performed by homologous
recombination in which the homologous intact sequence
from the sister chromatid is used to recover
the broken segment. It is considered that there is
a strong link between aberrant methylation of the
BRCA1 in white blood cells and breast cancer-related
molecular changes, which indicate the potential predisposition
of BRCA1 dysmethylation carriers for
developing breast cancer [20].
In the course of T2DM, the methylated fraction
of the CCND1 gene increases over 30-times. This
gene is a regulator of the cell cycle (cyclin-dependent
kinase). Together with CDK4 and CDK6, its protein
product is involved in a complex in the G1/S transition.
It has been reported that the methylation status
of CCND1 is not associated with its expression [21].
The methylated fraction of Prdx2 increases by
more than 30-times in the course of T2DM. This gene
encodes a member of the peroxiredoxin family of
antioxidant enzymes, which reduces hydrogen peroxide
and alkyl hydro-peroxides. The encoded protein
plays an antioxidant protective role in cells. Previous
studies have shown that the deletion of Prdx2
leads to increased expression of vascular cell adhesion
molecule-1, intracellular adhesion molecule-1
and monocyte chemo-attractant protein-1, which are
markers of endothelial dysfunction and also inducers
of atherosclerotic plaques [22,23]. This shows that
the increased methylation of Prdx2 in T2DM leads
to loss of its antioxidant protective and antiatherosclerotic
role.
The methylated fraction of SCARA3 shows a
more than 20-fold increase in the course of T2DM.
The SCARA3 gene encodes a macrophage scavenger
receptor-like protein. Its protein discharges reactive
oxygen radicals and plays an important role in
the protection against oxidative stress. It has been
shown that oxidative stress induces the expression of
SCARA3 [24]. The increased methylation of SCARA3
in T2DM patients is another epigenetic hint for the
loss of oxidative protection in the pathogenesis and
course of the disorder.
The methylated fraction of the universal tumor
suppressor gene Tp53 increases 10-times in
the course of T2DM. The p53 protein regulates key
cellular processes, including cell-cycle arrest, DNA
repair, apoptosis, and senescence in response to stress
signals. It becomes stabilized and activated in short
time in response to DNA damage, hypoxia, hyperproliferation,
and other types of cellular stress [25].
It is the most commonly inactivated gene in human
cancers. Taking into account that increased methylation
is one of the mechanisms for gene silencing,
the observed epigenetic pattern of Tp53 in our study
points to a possible molecular pathway in the eventual
cancer development in T2DM.
The increasing methylated fraction of BRCA1
and Tp53 observed in the present study was in line
with several meta-analyses, which show that T2DM
patients are at increased risk from cancer, as follows:
liver cancer 2.5-times higher [26]; endometrial 2.1
[27]; pancreatic 1.82 [28]; urinary bladder 1.43 [29];
kidney 1.42 [30]; colorectal 1.3 [31] and breast cancer
1.2-times higher risk [32].
In conclusion, the detected higher expression of
MBD2 in patients at different stage of T2DM indicated
general dysregulation of the DNA methylation
processes as a result of the disease. In line with this
result, of the analyzed stress and cell cycle regulation
genes, five showed consistenly increasing methylated
fraction with the increase in T2DM duration:
BRCA1, CCND1, Prdx2, SCARA3 and Tp53. The
elevated methylation of genes Prdx2 and SCARA3
showed that their role in oxidative stress protection
decreases due to elevated methylation and may cause
T2DM compli-cations. Genes BRCA1, CCND1 and
Tp53 are related to tumorigenesis. We refrain from
premature conclusion for CCND1 as its methylation
does not reflect its expression. On the other hand,
the increased methylation of BRCA1 and Tp53 was associated with cancer development, which was really
more common in T2DM patients [26-32]. This
finding unravels a possible epigenetic link between
T2DM and cancer development.
The results from the present study require
broadening of the set of genes analyzed for epigenetic
changes in T2DM. Furthermore, the results for
the genes with consistently increasing methylation
in T2DM should be further validated via expression
analysis. In case these results are confirmed,
the implementation of antioxidant protection in the
therapeutic approach for T2DM seems completely
justified from an epigenetic point of view.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
