Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity.
Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity.
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当转录因子（TF）结合可接近的顺式调控元件以建立特定的基因表达程序时，细胞分化。在分化胚胎干细胞（ES），染色质在谱系限制基因变得顺序访问，可能是凭借“先锋”TF活动，但组织可能利用其他策略在体内。侧抑制是一个普遍的过程，其中一个细胞迫使其邻居具有不同的身份，目前还不清楚等能祖细胞中的染色质如何经历侧抑制快速实现不同的，短暂可逆的细胞命运。在这里，我们报告了小鼠小肠隐窝分化的染色质和转录基础，其中Notch信号传导介导侧向抑制，将祖细胞分配到吸收或分泌谱系中。在分离的LGR 5+肠干细胞（ISC）和分泌和吸收祖细胞的转录谱表明，每个细胞群是不同的和祖细胞指定。然而，分泌和吸收祖细胞显示出相当水平的H3 K4 me 2和H3 K27 ac组蛋白标记和DNaseI超敏反应-标志着访问，允许染色质-在大多数相同的顺式元件。在LGR 5 + ISC中，在祖细胞中独特作用的增强子被很好地划分，揭示了染色质对不同转录程序的早期启动，并且在谱系被指定后很好地保留了活性标记。在这种染色质背景下，ATOH 1，一种分泌特异性TF，通过Delta样Notch配体基因控制侧向抑制，也驱动许多分泌谱系基因。消耗ATOH 1从指定的分泌细胞转化为功能性肠上皮细胞，表明显着的增强剂的存在或不存在的关键TF的反应延长。因此，侧抑制和肠隐窝谱系可塑性涉及谱系限制的TF与多能干细胞中建立的广泛允许的染色质的相互作用。
Cells differentiate when transcription factors (TFs) bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem (ES) cells, chromatin at lineage-restricted genes becomes sequentially accessible, probably by virtue of “pioneer” TF activity, but tissues may utilize other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbors, 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 signaling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages. Transcript profiles in isolated LGR5+ intestinal stem cells (ISC) 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 DNaseI hypersensitivity - signifying accessible, permissive chromatin - at most of the same cis-elements. Enhancers acting uniquely in progenitors were well-demarcated in LGR5+ ISC, 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 TF, controls lateral inhibition through Delta-like Notch ligand genes and also drives numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to presence or absence of a key TF. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted TF with broadly permissive chromatin established in multipotent stem cells.
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