Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Mol Cell Biol. 2011 May;31(10):2026-39. doi: 10.1128/MCB.01250-10. Epub 2011 Mar 14.
Transcription factors that potently induce cell fate often remain expressed in the induced organ throughout life, but their requirements in adults are uncertain and varied. Mechanistically, it is unclear if they activate only tissue-specific genes or also directly repress heterologous genes. We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was significantly accelerated in mice lacking both Cdx2 and its homolog Cdx1, with particular exaggeration of defects in villus enterocyte differentiation. Importantly, Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a transcription factor's mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a critical developmental regulator that activates tissue-specific genes.
转录因子能强力诱导细胞命运，但在诱导器官中表达的转录因子在整个生命过程中仍然存在，但其在成人中的需求不确定且多样。从机制上讲，目前还不清楚它们是仅激活组织特异性基因，还是直接抑制异源基因。我们条件性地使小鼠 Cdx2 失活，Cdx2 是肠道发育的主要调控因子，并对成年小肠绒毛中的 Cdx2 基因组占据情况进行了作图。尽管在 Cdx2 缺失胚胎中观察到的同异位转化在突变体成人中不存在，但基因表达和细胞形态受到严重损害。同时缺失 Cdx2 和其同源物 Cdx1 的小鼠的致死率显著加快，绒毛肠细胞分化缺陷尤为严重。重要的是，Cdx2 占据与数百个下降的转录本相关，但与 Cdx 缺失时同等数量上升的转录本不相关，这表明在肠道顺式调控区域中，Cdx2 主要发挥激活作用。因此，综合考虑转录因子的突变表型和顺式作用元件，揭示了一种关键发育调控因子在成人中持续存在的不同需求，该调控因子可激活组织特异性基因。
