Distinct Processes and Transcriptional Targets Underlie CDX2 Requirements in Intestinal Stem Cells and Differentiated Villus Cells.
Distinct Processes and Transcriptional Targets Underlie CDX2 Requirements in Intestinal Stem Cells and Differentiated Villus Cells.
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DOI：
10.1016/j.stemcr.2015.09.006
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发表时间：
2015-11-10
影响因子：
5.9
通讯作者：
Shivdasani RA
中科院分区：
文献类型：
--
作者：
San Roman AK;Tovaglieri A;Breault DT;Shivdasani RA
表达LGR5的肠道干细胞(ISCs)通过产生成熟的绒毛细胞(VCs)来更新成人的肠道上皮；ISC功能的转录基础尚不清楚。RNA测序分析表明，Lgr5+ISCs在向VCs分化过程中发生了转录调控，肠限制性转录因子(Tf)基因CDx2在两个群体中都有高表达。CDX2缺失的小鼠ISCs表现出增殖受损和长期不能产生成熟谱系，揭示了ISC的基本功能。染色质免疫沉淀测序分析CDX2在LGR5+ISCs中的表达，结合对照和CDX2−/−ISCs的基因表达谱，确定了CDX2调控不同于VCs的特征。在ISCs中，大多数CDX2结合发生在对未来基因表达的预期中，但CDX2主要激活VC基因，直接的ISC靶点被激活和抑制。干细胞和分化细胞对CDX2的不同需求可能反映了转录因子的多功能性，这种多样性指定了一个处于发育中的组织，并控制了成人中的同一组织。Tf CDX2在肠干细胞和绒毛细胞中高表达CDX2是肠干细胞增殖和分化所必需的，CDX2与干细胞中的CDX2结合预测未来绒毛细胞的基因表达直接激活或抑制ISCs中的CDX2靶标可能被激活或抑制Shivdasani及其同事展示了转录因子CDX2在肠干细胞(ISCs)复制和分化中的重要作用。考虑到CDX2结合以及上皮分化过程中转录的变化，他们表明ISCs中的结合预测了未来的基因表达。通过对CDX2缺失的ISCs的分析，他们确定了直接的靶基因，这些基因被激活或抑制，可能是缺陷的基础。
Lgr5-expressing intestinal stem cells (ISCs) renew the adult gut epithelium by producing mature villus cells (VCs); the transcriptional basis for ISC functions remains unclear. RNA sequencing analysis identified transcripts modulated during differentiation of Lgr5+ ISCs into VCs, with high expression of the intestine-restricted transcription factor (TF) gene Cdx2 in both populations. Cdx2-deleted mouse ISCs showed impaired proliferation and long-term inability to produce mature lineages, revealing essential ISC functions. Chromatin immunoprecipitation sequencing analysis of CDX2 in Lgr5+ ISCs, coupled with mRNA profiling of control and Cdx2−/− ISCs, identified features of CDX2 regulation distinct from VCs. Most CDX2 binding in ISCs occurs in anticipation of future gene expression, but whereas CDX2 primarily activates VC genes, direct ISC targets are activated and repressed. Diverse CDX2 requirements in stem and differentiated cells may reflect the versatility of TFs that specify a tissue in development and control the same tissue in adults. The TF Cdx2 is highly expressed in intestinal stem cells and villus cells CDX2 is required for proliferation and differentiation of intestinal stem cells CDX2 binding in stem cells anticipates future villus cell gene expression Direct CDX2 targets in ISCs may be activated or repressed Shivdasani and colleagues demonstrate an essential role for transcription factor CDX2 in replication and differentiation of intestinal stem cells (ISCs). Considering CDX2 binding together with transcriptional changes during epithelial differentiation, they show that binding in ISCs anticipates future gene expression. Through analysis of Cdx2-null ISCs, they identify direct target genes, which are activated or repressed and may underlie the defects.