Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity

A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts in vivo finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of lateral inhibition. Intestinal crypt differentiation Intestinal crypts are the focus of intensive study, stimulated in part by the recent discovery of distinct stem-cell populations and markers. Ramesh Shivdasani and colleagues have studied mechanisms underlying lateral inhibition and lineage plasticity in mouse small intestine crypts in vivo . They find that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and that this is the basis of lateral inhibition. Cells differentiate when transcription factors bind accessible cis -regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible 1 , 2 , 3 , 4 , probably by means of ‘pioneer’ transcription factor activity 5 , but tissues may use other strategies in vivo . Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours 6 , and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages 7 , 8 , 9 . Transcript profiles in isolated LGR5 + intestinal stem cells 10 and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same cis -elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5 + intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and a