The chromatin remodeling protein Lsh safeguards accessibility at potential enhancer regions and blocks access to lineage specific transcription factors

Chromatin structure controls access to DNA sequences, facilitates binding of transcription factors at enhancers and controls tissue specific gene expression. Dynamic regulation of chromatin accessibility is a key feature of cellular differentiation, but the factors involved in this process are not fully understood. We identified Lsh as important safeguard of enhancer accessibility. Lsh is a chromatin remodeling protein that controls DNA methylation level during development. Mutation of human Lsh (HELLS) causes the ICF syndrome, a severe human disorder with early lethality. Using MNase-seq we demonstrate specific genome-wide changes of chromatin structure in dependence of Lsh. While short term depletion of Lsh does not affect DNA methylation level, it leads to increased MNase digestibility at transcriptional regulatory elements. Our data suggests that Lsh impedes chromatin access at potential enhancers, which can be predicted based on DNAse hypersensitivity, specific histone modifications (H3K4me1) and based on transcription factor binding motifs. Furthermore, we demonstrate enhanced occupancy of ectopically expressed transcription factors after Lsh depletion attesting improved chromatin accessibility. Our data suggests that Lsh masks transcription factor binding sites and acts as guardian of chromatin accessibility at a subset of enhancers.