Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Genes Dev. 2018 Nov 1;32(21-22):1430-1442. doi: 10.1101/gad.318832.118. Epub 2018 Oct 26.
After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic -regulatory elements are decommissioned. Depletion of the intestinal TF CDX2 before this element transition stabilizes foregut enhancers, reinforces ectopic transcriptional programs, and hence imposes foregut identities on the midgut. Later in development, as the window of chromatin plasticity elapses, CDX2 depletion weakens intestinal, without strengthening foregut, enhancers. Thus, midgut endoderm is primed for heterologous cell fates, and TFs act on a background of shifting chromatin access to determine intestinal at the expense of foregut identity. Similar principles likely govern other fate commitments.
在获得选定的细胞命运的能力后，胚胎原基可能会在组织身份被不可逆转地确定（承诺）之前保持一定时间的可塑性。我们研究了这些发育里程碑的染色质基础，在具有可识别的前后模式和转录因子（TF）依赖性中间可塑性的小鼠内胚层中。前肠特异性增强子在早期中肠中与前肠内胚层一样可及和活跃，并且只有在异位调节元件被停用后，肠增强子和身份才会建立。在这个元素转换之前耗尽肠 TF CDX2 可以稳定前肠增强子，增强异位转录程序，从而将前肠身份强加给中肠。在发育后期，随着染色质可塑性窗口的流逝，CDX2 的耗尽会削弱肠，而不会增强前肠增强子。因此，中肠内胚层为异源细胞命运做好了准备，TF 在内胚层和前肠身份之间发挥作用，以改变染色质的可及性来决定肠。类似的原则可能适用于其他命运的承诺。
