Transcriptional and histone modification profiles were analysed in detail across
several regions of the mouse genome in order to examine how tissue-specificity is
determined at early stages of development and how it is maintained during cell
commitment. The analysis was mainly focused on a 2 Mb gene-dense region containing
68 known closely situated genes, having very diverse expression patterns.
Transcriptional profiling of this region showed that clustered tissue-restricted and
housekeeping genes are associated with clearly defined monovalent or bivalent
epigenetic domains. In ES cells, the actively transcribed housekeeping genes were
enriched for histone H3K4me1, H3K4me2, H3K4me3, H3K9ac and binding of Pol II.
Most of the silent tissue-restricted genes were marked by bivalent domains and had
background levels of Pol II. In few cases, substantial levels of Pol II were found at
inactive genes situated close to housekeeping genes, suggesting that transcriptional
read-through could be occurring at these genes in ES cells. Epigenetic profiling of the
gene-dense region in LPS-activated B cells showed that B cells have a very similar
histone modification profile to ES cells. Specifically, the analysis showed that bivalent
domains which were thought to be a defining characteristic of pluripotent stem cells are
equally prevalent in B cells, suggesting that the epigenetic marking of silent genes is
quite similar in these two very different cell types. Analysis of a large gene-poor region
containing four genes encoding GABAA neurotransmitter receptor subunits showed that
the this locus acquires a large bivalent domain of approximately 1.3 Mb following
differentiation of ES cells into NS cells and astrocytes. The results obtained in this study
demonstrate the complex and diverse nature of histone modifications at tissue-restricted
genes and suggest that trans-acting factors are responsible for generating highly specific
combinations of histone modifications at each individual gene at different stages of cell
differentiation
