Extended Data Figure 6: ATOH1 transcriptional control of secretory differentiation.

a, Model for cell-specific ATOH1 binding to permissive chromatin in crypt progenitors. b, Phastcons plot showing high evolutionary conservation of ATOH1-occupied sites in Sec-Pro cells and maximal enrichment of the consensus ATOH1 recognition motif near their peaks. c, Composite profiles of average H3K4me density near ATOH1 binding sites in Sec-Pro cells (left) and mouse brain (right). H3K4me marks are highly correlated with ATOH1 occupancy in the same, but not in the heterologous, tissue, as representative ChIP-seq data illustrate below. d, e, Examples of ATOH1 occupancy at loci for key secretory lineage transcription factors and secretory-specific genes: Nkx2-2 and Foxa2 (enteroendocrine cells), Xbp1 (Paneth cells), Tff3 (goblet cells), Spink4 and Hgfac (goblet and Paneth cells) and Sstr1 (endocrine cells). ATOH1 does not bind near Ent-Pro-specific genes, as shown at a sample locus, Bcl2l15. f, Schematic representation of ATOH1’s dual function in direct control of two gene groups: delta ligands for lateral inhibition and key secretory-specific transcription factors to promote secretory lineage differentiation. g, Relation of ATOH1 occupancy at enhancers with Sec-Pro-specific transcription. Bins of 200 genes, ranked by differential expression in Sec-Pro (left) or Ent-Pro (right), are represented along the x axis, and normalized ATOH1 binding in Sec-Pro (red) or brain (blue) at enhancers within 20 kb of the genes in each bin is represented on the y axis. The graphs show the first (Sec-Pro-specific), middle (no differential expression), and last (Ent-Pro-specific) three bins of 200 genes each. Error bars indicate standard errors of the mean and pair-wise t-tests support a role for ATOH1 in activating Sec-Pro genes, without an overt role in silencing Ent-Pro genes.