Nature2014-06-25 5:17 PM

肠腺分化的机制 Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity


肠腺(肠隐窝)受到深入研究,部分原因是最近发现了截然不同的干细胞类群和标记物。Ramesh Shivdasani及同事对小鼠小肠肠腺中侧向抑制(lateral inhibition)和线性弹性的机制进行了活体研究。他们发现,肠腺细胞维持一个容许性的染色质状态——在该状态下一个转录因子来决定形成哪个细胞系,这一点是侧向抑制的基础。


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, probably by means of ‘pioneer’ transcription factor activity, 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, 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. Transcript profiles in isolated LGR5+ intestinal stem cells10 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 also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.






Nature Magazine

0 Following 27 Fans 0 Projects 626 Articles


Meristems encompass stem/progenitor cells that sustain postembryonic growth of all plant organs. How meristems are activated and sustained by nutrient

Read More

Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of P

Read More

Abstract The effect of anthropogenic aerosols on cloud droplet concentrations and radiative properties is the source of one of the largest uncertainti

Read More

Abstract Ecological and societal disruptions by modern climate change are critically determined by the time frame over which climates shift beyond his

Read More

Abstract Evidence from Greenland ice cores shows that year-to-year temperature variability was probably higher in some past cold periods, but there is

Read More

Abstract The land and ocean act as a sink for fossil-fuel emissions, thereby slowing the rise of atmospheric carbon dioxide concentrations1. Although t

Read More

论文摘要 人们已经非常清楚生物多样性对初级生产力等生态系统功能有一个积极影响,但它对植物凋落物的多样性和分解植物凋落物的生物的多样性的影响却不是很清楚。Stephan H?ttenschwiler及同事对从亚北极到热带、包括水生生态系统和陆地生态系统在内的五个地点所进行的并行操纵实验中的凋落物多样性进

Read More

论文摘要 FANTOM5 (即“哺乳动物基因组-5的功能注解”) 是一个大型国际合作项目的第5大阶段,其目标是分析定义每个人类细胞类型的转录调控网络。本期Nature上的两篇Articles论文发表了该项目的一些最新结果。第一篇论文利用FANTOM5项目组的组织和原代细胞样本来定义整个人体中活性的、在

Read More

论文摘要 有证据表明,血管 (尤其是它们的内皮细胞) 控制器官的生长、平衡和再生。在本期Nature上发表的两篇论文中,Ralf Adams及同事证明,骨头血管含有专门支持骨成熟和再生的内皮细胞。Anjali Kusumbe等人在小鼠骨骼系统内识别出一个在介导骨生长中起关键作用的毛细血管亚型。这些血管

Read More

论文摘要 CD4 T细胞(携带能够识别被病毒感染的细胞表面上的CD4抗原的受体的辅助T细胞)的丧失是艾滋病发病的根源。在这项研究中,Warner Greene等人识别出静止的淋巴CD4 T细胞在HIV感染过程中被耗尽的机制。利用保持了天然淋巴环境的人淋巴组织的体外培养,本文作者发现,失败的病毒复制触发

Read More