INVESTIGATIVE REPORT
585 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Ten-eleven Translocation-2 Regulates DNA Hydroxymethylation Status and Psoriasiform Dermatitis Progression in Mice
Xin WANG 1 , 2 # , Xinxin LIU 1 # , Xiaoru DUAN 1 , Ke ZHU 1 , Song ZHANG 1 , Lu GAN 1 , Nian LIU 1 , Himanshu JAYPAUL 1 , Johanna T . MAKAMURE 1 , Zhangyin MING 3 and Hongxiang CHEN 1
1
Department of Dermatology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430022 , China , 2 Department of Dermatology , Affiliated Hospital of Nantong University , Nantong , China , and 3 Department of Pharmacology , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , China
#
These authors contributed equally to this work .
Epigenetics plays an important role in the development and progression of many diseases . There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis . The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine ( 5-hmC ) and ten-eleven translocation-2 ( TET2 ) in psoriasiform dermatitis in mice . Immunohistochemical staining was performed on psoriasis patients and healthy controls . Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis . In comparison with healthy controls , 5-hmC was more extensive and intense in the skin lesions from psoriasis patients . TET2 and 5-hmC were highly expressed in imiquimod-induced psoriasiform skin lesions . Importantly , knockdown of TET2 expression in mice attenuated the psoriasiform phenotype and the expression levels of proinflammatory cytokines ( interleukin-17A and -17F and interferon-γ ) and the chemokine CXCL1 in the lesional skin of mice . This is the first demonstration of a critical role for TET2 in psoriasiform dermatitis in a mouse model , and indicates that 5-hmC may serve as a potential biomarker of psoriasis .
Key words : ten-eleven translocation 2 ; 5-hydroxymethylcytosine ; psoriasis ; epigenetics ; Th17 cell .
Accepted Mar 15 , 2018 ; Epub ahead of print Mar 15 , 2018 Acta Derm Venereol 2018 ; 98 : 585 – 593 .
Corr : Hongxiang Chen , Department of Dermatology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Jiefang Avenue 1277 #, Wuhan 430022 , China . E-mail : hongxiangchen @ hotmail . com
Psoriasis is a common chronic inflammatory skin disease associated with well-demarcated , erythematous plaques and silvery scales ( 1 ). The pathogenic manifestations of psoriasis are characterized by immune cell infiltration and the aberrant proliferation and differentiation of epidermal cells ( 2 ). Although the aetiology of psoriasis is incompletely understood , the interplay between genetic and environmental triggers is known to have an important role in the development of psoriasis ( 3 ). Some studies have suggested that abnormal DNA methylation is present in psoriatic skin compared with normal or uninvolved psoriatic skin ( 4 , 5 ). However ,
SIGNIFICANCE
Psoriasis is one of the most common chronic inflammatory skin diseases which is a complex disorder involving multiple pathogenic factors . This study explored the role of epigenetic modifications in the pathogenesis of psoriasis . Our study found that 5-hydroxymethylcytosine and ten-eleven translocation-2 ( TET2 ) levels were increased in psoriatic lesions , compared with normal skin . Knockdown of TET2 expression alleviated the severity of imiquimod-induced psoriasiform dermatitis in mice . Our data highlight a possible role for TET2 in the pathogenesis of psoriasiform dermatitis .
DNA hydroxymethylation and the mechanisms of psoriasis remain poorly understood .
Epigenetic modifications , such as DNA methylation , DNA hydroxymethylation and histone modifications , are crucial for regulating the occurrence and development of a variety of skin diseases , such as systemic lupus erythematosus . This suggests a significant role for epigenetic regulation in dermatology ( 6 , 7 ). Recently , several studies in both human and mice have identified that the ten-eleven translocation ( TET ) family dioxygenases TET1 , TET2 and TET3 oxidize 5-methylcytosine ( 5-mC ) to 5-hmC , 5-formylcytosine ( 5-fC ) and 5-carboxylcytosine ( 5-caC ) in DNA , and promote DNA demethylation ( 8 – 10 ) . The newly characterized 5-hmC is commonly differentially expressed in various types of disorders . TET2 is expressed in several differentiated tissues and has been studied in a variety of diseases , such as haematopoietic diseases , immune system disorders and cancer ( 11 – 14 ). TET2 has been positively associated with 5-hmC and regulation of other elements ( 15 ). Dysregulation of TET2 affects diverse biological processes , including cell differentiation , development , and proliferation , indicating that TET2 is a key epigenetic regulating factor .
Although TET2 functions as a tumour suppressor within the hematopoietic system ( 13 ), it is unclear whether TET2 is involved in the pathogenesis of psoriasis . TET2 has been shown to be associated with enriched areas of 5-hmC and to promote signature cytokine expression patterns of Th1 and Th17 cells ( 12 ). TET2 selectively mediates transcription of IL-6 during inflammation resolution in dendritic cells by recruiting Hdac2
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2926 Acta Derm Venereol 2018 ; 98 : 585 – 593