Role of linker histone H1 in epigenetic regulation of pluripotency genes and Hox genes
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Linker histone H1 plays a key role in facilitating folding of higher order chromatin structure. Previous studies have shown that deletion of three somatic H1 subtypes together leads to embryonic lethality and that H1c/H1d/H1e triple knockout (TKO) embryonic stem cells (ESCs) display bulk chromatin decompaction. Following this initial work, we investigated the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, as well as the regulation of Hox genes expression. We find that H1 TKO ESCs are more resistant to spontaneous differentiation, impaired in embryoid body differentiation, and largely blocked in neural differentiation. We present evidence that H1 contributes to efficient repression of the expression of pluripotency factors, Oct4 and Nanog, and participates in establishment and maintenance of DNA methylation and histone modification necessary for silencing pluripotency genes during stem cell differentiation and embryogenesis. In addition, we find reduced expression of a distinct set of Hox genes in embryos and ESCs, respectively. Furthermore, by characterizing H1c−/−; H1d−/−; and H1e−/− single-H1 null ESCs established in this study, we showed that individual H1 subtypes regulated specific Hox genes in ESCs. Finally, we demonstrate that the levels of H3K4me3 were significantly diminished at the affected Hox genes in H1 TKO- and single-H1 KO- ESCs, whereas H3K27me3 occupancy is modestly increased at specific Hox genes. Our results suggest that marked reduction of H1 levels and decondensation of bulk chromatin affect the expression of pluripotency genes and Hox genes in embryos and ESCs, which may be in part mediated through establishment and maintenance of epigenetic marks.