The dynamic landscape of genomic 5-hydroxymethylcytosine in mycosis fungoides reveals biomarkers for progression and prognosis.

Summary: Abstract Body: Mycosis fungoides (MF) is characterized by epigenetic aberrations, notably the loss of 5-hydroxymethylcytosine (5hmC), which serves as an epigenetic hallmark. However, as a key epigenetic marker in DNA methylation, the genomic landscape of 5hmC distribution and its implication MF progression and prognosis remains unraveled. We conducted 5hmC sequencing on a total of 97 skin lesions including 43 early-stage MF lesions, 32 advanced-stage MF lesions and 22 benign inflammatory dermatoses lesions. We found that, in the background of global reduction, 5hmC was enriched in the coding region of genes (gene body) as MF progresses. Gene body 5hmC levels positively correlated with the RNA expression levels of the corresponding genes in paired MF lesions. Gene body 5hmC levels followed the progressive trajectory from early stage to advanced stage MF. Genes with significantly high 5hmC levels in the late pseudotime trajectory were involved in T cell proliferation pathway, cell cycle pathway and central memory T cell phenotype. Among these genes, elevated expressions of central memory T cell marker LEF1 and CD27 were validated by immunohistochemistry staining and proposed as novel biomarkers for clinical prognosis in MF. Potential distal enhancer regions for LEF1 and CD27 were identified by 5hmC level correlation. Motifs of the ETS transcription factor family were significantly enriched in advanced stage, suggesting potential mechanisms driving MF progression. This study depicts a dynamic landscape of genomic 5hmC through MF progression and identifies novel molecular markers associated with prognosis. These findings contribute to the understanding of the epigenetic dysregulation in MF. Mengzhou Cao¹, Jinmin Yang², Yumei Gao³, Bo He⁴, Chengqi Yi², Yang Wang¹ 1. Dermatology and Venereology, Peking University First Hospital, Beijing, China. 2. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. 3. Dermatology and Venerology, Beijing Tsinghua Changgung Hospital, Beijing, China. 4. Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, China. UV Biology/Injury and Non-melanoma Cancers