Epigenetic regulation is now known to play an important role in determining stem cell fate during normal tissue development and disease pathogenesis. In this study, we report loss of 5-hydroxymethylcytosine (5-hmC) mediated by ten-eleven translocation (TET) methylcytosine dioxygenases in keratinocyte stem cells (KSCs) and in their progenitor transit-amplifying (TA) cells of psoriatic lesions. We establish the DNA hydroxymethylation profile in both human psoriasis as well as in the imiquimod (IMQ)-induced mouse psoriasis model. Genome-wide mapping of 5-hmC in IMQ-treated mice epithelium revealed a loci-specific reduction of 5-hmC in genes associated with maintaining stem cell homeostasis including those involved in the RAR and Wnt/β-catenin signaling pathways. Restoration of TET expression in human KSC cultures via vitamin C treatment increased 5-hmC levels and induced more normal KSC differentiation. We found that by modulating 5-hmC levels in vitro, we could alter downstream expression of genes important in regulating stem cell homeostasis like nestin as well as IL-17R known to promote the psoriatic phenotype. Our findings demonstrate that loss of 5-hmC is a critical epigenomic phenomenon in KSCs and TA cells during psoriasis pathogenesis. / 2019-12-17T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36696 |
| Date | 17 June 2019 |
| Creators | Yuan, Christine Wan-Yin |
| Contributors | Cui, Rutao |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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