Abstract：
Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.
摘要：
隐窝处的肠干细胞分裂并产生祖细胞，该祖细胞在转运扩增（TA）区中增殖并分化成各种成熟细胞类型。这里,我们表明转录因子ARID3A调节TA祖细胞的肠上皮细胞增殖和分化。ARID3A形成由TGF-β和WNT介导的从绒毛尖端到上隐窝的表达梯度。Arid3a的肠特异性缺失减少隐窝增殖，主要在TA细胞中。大量和单细胞转录组学分析显示Arid3acKO肠中的肠细胞增加和分泌分化减少，伴随着两个细胞谱系的丰富的上绒毛基因签名。我们发现，缺乏Arid3a的肠道中上皮分化的增强是由HNF1和HNF4的结合和转录增加引起的。最后,我们表明，Arid3a的丢失会损害辐照诱导的再生，并伴有持续的细胞死亡和重编程。我们的发现暗示Arid3a具有微调TA祖细胞的增殖分化动力学的功能，这对损伤诱导的再生至关重要。
