Naslov
EPIGENETIC REGULATION OF PTPN12 GENE COULD INFLUENCE THE IMMUNOPATHOGENESIS OF JUVENILE SPONDYLOARTHRITIS AND GIVE RISE TO NEW THERAPEUTIC OPTIONS

Autori
Lamot, Lovro ; Borovecki, Fran ; Kapitanovic, Sanja ; Gotovac, Kristina ; Vidovic, Mandica ; Lamot, Mirta ; Paleka Bosak, Edi ; Harjacek, Miroslav

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Pediatric Rheumatology / - , 2016

Skup
PReS 2016

Mjesto i datum
Genova, Italija, 28.09.2016. - 01.10.2016

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
PTPN12; epigenetics; juvenile spondyloarthritis; jSpA

Sažetak
Introduction: Gene expression profiling of juvenile spondyloarthritis (jSpA) patients revealed aberrant expression of some genes, but the mechanism of this expression alterations remained unknown (1).  Objectives: To discover epigenetic modifications with effect on regulation of 4 genes (TLR4, NLRP3, CXCR4, PTPN12) differentially expressed in jSpA patients.  Methods: DNA methylation analysis was performed in promotor region of differentially expressed genes by methylated DNA Immunoprecipitation (meDIP). Based on literature search, 4 microRNAs (miR-150, miR- 146a, miR-181a, miR-223) included in regulation of differentially expressed genes were selected and their expression was analyzed using RT-PCR with predeveloped Taqman microRNA assays. Both analysis were performed in 7 newly diagnosed untreated jSpA patients and 7 matched healthy children. Results: Statistical analysis revealed no difference in methylation of promotor sites for examined genes, but PTPN12 showed trend towards higher methylation (p=0, 076), compared with control group. There was no statistical difference in expression of selected miRs between two groups. Conclusion: jSpA is a multifactorial disease in which a complex interplay occurs between the immune system and environmental factors on a predisposing genetic background. One of the most important mechanisms by which environment can influence processes inside of an organism is gene regulation via epigenetic modifications. Therefore, we investigated possible influence of DNA methylation and posttranscriptional modifications on the genes differentially expressed in jSpA patients. The results didn't indicate any statistically significant abundance of miRs with described role in expression of examined genes, nor hypermethylation of their promotor sites, but there was a clear trend of higher methylation of PTPN12 in jSpA patients, while lack of statistical significance could be attributed to small number of study participants. This observation can easily explain decrease of PTPN12 expression in treated and untreated jSpA patients. PTPN12 expressed in dendritic cells is identified as a key regulator of dendritic cell migration as well as T cell-dependent immunity and autoimmunity (2). It is also a negative regulator of inflammation and intestinal cell migration, as well as a positive regulator of osteoclast activity, all of which are processes important for the pathophysiology of jSpA. Results of our study are in concordance with previous epigenetic studies of this gene in human breast cancer patients, which showed PTPN12 can be silenced by methylation. Interestingly, more recent study pointed to the potential of 5-Azac, a DNA hypomethylating agent, in increasing PTPN12 expression, and highlighted the therapeutic potential of this mechanism in treatment of breast cancer (6). Therefore, it is tempting to speculate the results of our study could after confirmation in larger cohorts give rise for new treatment options in jSpA patients as well. REFERENCES: 1. Lamot L, et al. Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis. PLoS One. 2014 Dec 15 ; 9(12):e115416. 2. Inmoo Rhee, et al. Control of dendritic Cell Migration, T Cell-Dependent Immunity, and Autoimmunity by Protein Tyrosine Phosphatase PTPN12 Expressed in Dendritic Cells. Mol Cell Biol. 2014 Mar ; 34(5):888-99. 3. Thummuri D, et al. Epigenetic regulation of protein tyrosine phosphatase PTPN12 in triple-negative breast cancer. Life Sci. 2015 Jun 1 ; 130:73- 80.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Kliničke medicinske znanosti

POVEZANOST RADA