The term functional domain is often used to describe the region containing the cis acting sequences that regulate a gene locus. “Strong” domain models propose that the domain is a spatially isolated entity consisting of a region of extended accessible chromatin bordered by insulators that have evolved to act as functional boundaries. However, the observation that independently regulated loci can overlap partially or completely raises questions about functional requirements for physically isolated domain structures. An alternative model, the “weak” domain model, (...) proposes that domain structure is determined by the distribution of binding sites for positively acting factors, without a requirement for functional boundaries. The domain would effectively be the region that contains these factor-binding sites. Specificity of promoter-enhancer interactions would play a major role in maintaining the functional autonomy of adjacent genes. Sequences that interfere with these interactions (frequently characterised as insulators) would be selected against if they occurred within the domain but not at the edges, or in the interdomain regions. As a result, insulators would often be found near the borders of domains without necessarily being selected to act as boundaries. BioEssays 22:657–665, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Priming of lineage‐specific genes in pluripotent embryonic stem cells facilitates rapid and coordinated activation of transcriptional programmes during differentiation. There is growing evidence that pluripotency factors play key roles in priming tissue‐specific genes and in the earliest stages of lineage commitment. As differentiation progresses, pluripotency factors are replaced at some primed genes by related lineage‐specific factors that bind to the same sequences and maintain epigenetic priming until the gene is activated. Polycomb and trithorax group proteins bind many genes in pluripotent (...) cells generating bivalent domains that contain both active and repressive histone modifications. The properties of polycomb proteins suggest that they act as gatekeepers, helping to maintain silencing in pluripotent stem cells while establishing a chromatin environment that is permissive for priming by sequence‐specific factors. The overall effect of factor‐mediated priming is to initiate the input of information required for cell differentiation before the first lineage choices have been made. (shrink)

As well as having the remarkable ability to differentiate into all of the cell types in the embryo, embryonic stem (ES) cells also have the capacity to divide and self‐renew. Maintenance of pluripotency through repeated cell divisions indicates that the developmental plasticity of ES cells has a specific epigenetic basis. We propose that tightly localised regions of histone modification are formed in ES cells by binding of sequence‐specific transcription factors at genes that are destined for expression at later stages of (...) differentiation. These ‘early transcription competence marks’ would help to maintain pluripotency by preventing the spread of repressive chromatin modifications. We further propose that the presence of discrete histone modification marks in pluripotent cells facilitates the binding of lineage‐specific and general transcription factors to the marked regions as ES cells commit to different fates. By helping to organise the precisely timed responses of genes to the signals that determine lineage choice, the gene‐specific localised epigenetic marks would play a key role in the establishment of complex gene expression programmes in differentiating cells. BioEssays 27:1286–1293, 2005. © 2005 Wiley Periodicals, Inc. (shrink)