H1 linker histones are a class of DNA-binding proteins involved in the formation of supra-nucleosomal chromatin higher order structures. Eleven non-allelic subtypes of H1 are known in mammals, seven of which are expressed in somatic cells, while four are germ cell-specific. Besides having a general structural role, H1 histones also have additional epigenetic functions related to DNA replication and repair, genome stability, and gene-specific expression regulation. Synthesis of the H1 subtypes is differentially regulated both in development and adult cells, thus suggesting that each protein has a more or less specific function. The somatic variant H1.0 is a linker histone that was recognized since long ago to be involved in cell differentiation. Moreover, it has been recently found to affect generation of epigenetic and functional intra-tumor heterogeneity. Interestingly, H1.0 or post-translational forms of it have been also found in extracellular vesicles (EVs) released from cancer cells in culture, thus suggesting that these cells may escape differentiation at least in part by discarding H1.0 through the EV route. In this review we will discuss the role of H1.0 in development, differentiation, and stem cell maintenance, also in relation with tumorigenesis, and EV production.
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