Contribution of Retrotransposons to the Pathogenesis of Type 1 Diabetes and Challenges in Analysis Methods

Štangar, Anja; Kovač, Jernej; Šket, Robert; Tesovnik, Tine; Zajec, Ana; Kern, Barbara Čugalj; Bizjan, Barbara Jenko; Battelino, Tadej; Dovč, Klemen

doi:10.3390/ijms24043104

Cited by 2 publications

(1 citation statement)

References 77 publications

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“…In addition to gene polymorphisms, changes in the structure of the genome, which could be due to repeated elements or endogenous viral elements (EVEs), may play a role in the susceptibility to T1D. These elements encompass human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, which include long and short interspersed nuclear elements [11][12][13][14]. Most high copies of non-LTR retroelements are long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs) such as the Alus, constituting 16.9% and 10.6% of the human genome, respectively [15].…”

Section: Introductionmentioning

confidence: 99%

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

Katsanou,

Kostoulas,

Liberopoulos

et al. 2023

Genes

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Evidence suggests that genome-wide hypomethylation may promote genomic instability and cellular senescence, leading to chronic complications in people with diabetes mellitus. Limited data are however available on the Alu methylation status in patients with type 1 diabetes (T1D). Methods: We investigated DNA methylation levels and patterns of Alu methylation in the peripheral blood of 36 patients with T1D and 29 healthy controls, matched for age and sex, by using the COmbined Bisulfite Restriction Analysis method (COBRA). Results: Total Alu methylation rate (mC) was similar between patients with T1D and controls (67.3% (64.4–70.9%) vs. 68.0% (62.0–71.1%), p = 0.874). However, patients with T1D had significantly higher levels of the partial Alu methylation pattern (mCuC + uCmC) (41.9% (35.8–45.8%) vs. 36.0% (31.7–40.55%), p = 0.004) compared to healthy controls. In addition, a positive correlation between levels of glycated hemoglobin (HbA1c) and the partially methylated loci (mCuC + uCmC) was observed (Spearman’s rho = 0.293, p = 0.018). Furthermore, significant differences were observed between patients with T1D diagnosed before and after the age of 15 years regarding the total methylation mC, the methylated pattern mCmC and the unmethylated pattern uCuC (p = 0.040, p = 0.044 and p = 0.040, respectively). Conclusions: In conclusion, total Alu methylation rates were similar, but the partial Alu methylation pattern (mCuC + uCmC) was significantly higher in patients with T1D compared to healthy controls. Furthermore, this pattern was associated positively with the levels of HbA1c and negatively with the age at diagnosis.

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Section: Introductionmentioning

confidence: 99%

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

Katsanou,

Kostoulas,

Liberopoulos

et al. 2023

Genes

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The role of retroelements of the human genome in the development of type 1 diabetes mellitus

Mustafin

2024

Kazan Med J

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Retroelements (retrotransposons and endogenous retroviruses) are a class of mobile genetic elements that move in the genome by inserting their own reverse transcribed transcripts. They serve as drivers of epigenetic regulation; therefore, individual characteristics of the distribution of retroelements in the genome influence the development of multifactorial diseases. Type 1 diabetes mellitus is a multifactorial disease with an immune response against pancreatic β cells. The role of heredity in the development of the disease is estimated at 88%, and the role of allelic variants of various genes is determined. There are also other specific types of diabetes mellitus, which account for more than 2% of cases of diabetes mellitus and are monogenic diseases with an autosomal dominant mode of inheritance due to germline mutations in the MODY genes, including HNF4A, GCK, HNF1A, HNF1B. Most patients with type 1 diabetes have the protein product and ribonucleic acid (RNA) of the insulin inhibitor HERV-W-Env, which is caused by abnormal expression of the human endogenous retrovirus (HERV). An assumption has been made about the role of retroelements in the development of type 1 diabetes mellitus. This is due to their involvement in the phylogenetic formation of the endocrine system, since in evolution retroelements turned out to be sources of regulatory sequences of hormone genes, nuclear hormone receptors and binding sites for them. Type 1 diabetes mellitus is associated with the integration of HERV into the HLA-DQ gene region, with allelic variants and sizes of VNTR variable tandem repeats (part of the SVA retroelements), which regulate the expression of the insulin gene and other hormones. For this reason, it is likely that the development of type 1 diabetes mellitus may be based on individual characteristics of the distribution of HERVs in the human genome and their dynamic changes in ontogenesis. HERVs also play a role in the etiopathogenesis of diabetes mellitus through the activation of an autoimmune response, the triggering factors of which are exogenous viral infections and stress. Thus, retroelements are involved in various mechanisms of the development of type 1 diabetes mellitus, which reflects their global regulatory influence on endocrine regulation.

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Contribution of Retrotransposons to the Pathogenesis of Type 1 Diabetes and Challenges in Analysis Methods

Cited by 2 publications

References 77 publications

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

The role of retroelements of the human genome in the development of type 1 diabetes mellitus

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