The Genomic Landscape of the Somatic Linker Histone Subtypes H1.1 to H1.5 in Human Cells

•Mapping of the genomic distribution of all somatic H1 replication-dependent subtypes•Regulatory regions associated with active transcription are depleted of H1•H1 binding at CG-rich regions depends on their position and DNA methylation•H1 subtypes mark distinct topological domains and lamina-associated domains

SummaryHuman cells contain five canonical, replication-dependent somatic histone H1 subtypes (H1.1, H1.2, H1.3, H1.4, and H1.5). Although they are key chromatin components, the genomic distribution of the H1 subtypes is still unknown, and their role in chromatin processes has thus far remained elusive. Here, we map the genomic localization of all somatic replication-dependent H1 subtypes in human lung fibroblasts using an integrative DNA adenine methyltransferase identification (DamID) analysis. We find in general that H1.2 to H1.5 are depleted from CpG-dense regions and active regulatory regions. H1.1 shows a DamID binding profile distinct from the other subtypes, suggesting a unique function. H1 subtypes can mark specific domains and repressive regions, pointing toward a role for H1 in three-dimensional genome organization. Our work integrates H1 subtypes into the epigenome maps of human cells and provides a valuable resource to refine our understanding of the significance of H1 and its heterogeneity in the control of genome function.

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