Seven linker histone H1 variants are present in human somatic cells with distinct prevalence across cell types. Despite being key structural components of chromatin, it is not known whether the different variants have specific roles in the regulation of nuclear processes or are differentially distributed throughout the genome. Using variant-specific antibodies to H1 and hemagglutinin (HA)-tagged recombinant H1 variants expressed in breast cancer cells, we have investigated the distribution of six H1 variants in promoters and genome-wide. H1 is depleted at promoters depending on its transcriptional status and differs between variants. Notably, H1.2 is less abundant than other variants at the transcription start sites of inactive genes, and promoters enriched in H1.2 are different from those enriched in other variants and tend to be repressed. Additionally, H1.2 is enriched at chromosomal domains characterized by low guanine–cytosine (GC) content and is associated with lamina-associated domains. Meanwhile, other variants are associated with higher GC content, CpG islands and gene-rich domains. For instance, H1.0 and H1X are enriched at gene-rich chromosomes, whereas H1.2 is depleted. In short, histone H1 is not uniformly distributed along the genome and there are differences between variants, H1.2 being the one showing the most specific pattern and strongest correlation with low gene expression.

Ministerio de Ciencia e Innovació n of Spain (MICINN) and FEDER [BFU2011-23057 to A.J.]; Ministerio de Economía y Competitividad [SAF2012-36199 to N.L.-B.]; Generalitat de Catalunya [2009-SGR-1222 to A.J.]; JAE-Doc contract from CSIC-MICINN (to J.-M.T.); TA contract from CSIC-MICINN (to R.M.); FPU predoctoral fellowship from MICINN (to L.M.-A.). Funding for open access charge: Ministerio de Ciencia e Innovación of Spain (MICINN) and FEDER [BFU2011-23057 to A.J.]