DNA hypomethylation comprising transposable elements defines human regulatory T cells in cutaneous tissue and identifies their blood recirculating counterpart

Regulatory T cells (Treg cells) in tissues play crucial immunoregulatory and tissue-regenerative roles. Despite their significance, the epigenetic basis of human tissue-Treg cells, their differentiation as well as a migratory subset of tissue-Treg cells are incompletely understood. Here, we performed genome-wide DNA methylation analysis of human Treg cells from skin and blood and integrated these data into a multi-omic framework including chromatin accessibility and gene expression. This analysis revealed novel programs governing human skin Treg cell differentiation and delineated the presence of these programs across molecular levels. We discovered that subfamilies of transposable elements are a major constituent of the hypomethylated landscape of tissue-Treg cells. Based on DNA hypomethylation homologies, our data unveil that the population of blood CCR8+ Treg cells contains recirculating human skin Treg cells. Our findings provide novel insights into the biology of human tissue-Treg cells, which are essential to harness these cells for therapeutic purposes. This GEO record comprises the whole-geome bisulfite sequencing data used in the study. Whole genome bisulfite sequencing of purified human skin Treg cells, skin Tconv cells, subcutaneous fat Treg cells, blood CCR8+ Treg cells, blood CD45RA+ Treg cells and blood CD45RA+ Tconv cells. Each cell type is represented by three biological replicates from individual donors. *************************************************************** Raw files for human/patient samples are being made available in EGA (https://ega-archive.org/datasets/EGAD50000001022) for controlled access to the personally identifiable sequence data. ***************************************************************