UHRF1 Controls Thymocyte Fate Decisions Through the Epigenetic Regulation of EGR1 Expression

Abstract

Abstract Thymocyte differentiation is a highly complex process that is accompanied by epigenetic changes. Ubiquitin-like containing PHD ring finger 1 (UHRF1) is a critical epigenetic modifier involved in various cellular processes. Here, we demonstrated that it is highly expressed in T-cell precursors of the thymus. Further, its deficiency results in significantly-reduced thymocyte cellularity and thymus size. Through systematic analysis based on single-cell RNA-sequencing, we found that UHRF1 deficiency thwarts αβ T cell lineage development while biasing γδ lineage differentiation, dampens the progression of immature single-positive cells (ISPs). Further, the analysis of gene-regulatory networks demonstrated that UHRF1 controls the expression of early growth response 1 (EGR1). UHRF1 interacts with DNA methyltransferase 1 (DNMT1) at the CpG promoter region of Egr1 loci and affects the nearby chromatin modifications of H3K9me3 and H3K4me3. Taken together, our results demonstrate that UHRF1 is a key factor that mediates the epigenetic regulation of EGR1 and consequently thymocyte fate decisions.