Abstract
Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells.
Highlights
In humans, there are eleven subtypes of linker histones that stabilize higher order chromatin structure and are generally associated with repressed genes [1,2,3,4,5]
We found that H1.5, but not H1.3 (HIST1H1D), forms blocks of chromatin binding in genic and intergenic regions in differentiated human cells from all germ layers but not in embryonic stem cells
H1.5 binding is associated with other repressive chromatin elements such as SIRT1 binding and H3K9me2 enrichment, and it negatively correlates with polymerase II (Pol II) distribution
Summary
There are eleven subtypes of linker histones that stabilize higher order chromatin structure and are generally associated with repressed genes [1,2,3,4,5]. Depletion of mouse H1c, H1d and H1e leads to less compact packaging of chromatin, changes in core histone modifications, and reduced DNA methylation at certain loci [6]. Linker histones exhibit altered expression with at least one linker histone gene, namely H1.5, being mutated in colon cancer [8]. Important participants in normal biological as well as disease processes. While some functional differences have been reported for certain linker histones [9], our knowledge of global distribution or function of each linker histone remains rudimentary
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