Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA.
Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Republic of Korea.
Nucleic Acids Res. 2018 Nov 16;46(20):10796-10809. doi: 10.1093/nar/gky891.
The mammary luminal lineage relies on the common cytokine-sensing transcription factor STAT5 to establish super-enhancers during pregnancy and initiate a genetic program that activates milk production. As pups grow, the greatly increasing demand for milk requires progressive differentiation of mammary cells with advancing lactation. Here we investigate how persistent hormonal exposure during lactation shapes an evolving enhancer landscape and impacts the biology of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor occupancy at mammary enhancers, suggesting that their activities evolve with advancing differentiation. Using mouse genetics, we demonstrate that the functions of individual enhancers within the Wap super-enhancer evolve as lactation progresses. Most profoundly, a seed enhancer, which is mandatory for the activation of the Wap super-enhancer during pregnancy, is not required during lactation, suggesting compensatory flexibility. Combinatorial deletions of structurally equivalent constituent enhancers demonstrated differentiation-specific compensatory activities during lactation. We also demonstrate that the Wap super-enhancer, which is built on STAT5 and other common transcription factors, retains its exquisite mammary specificity when placed into globally permissive chromatin, suggesting a limited role of chromatin in controlling cell specificity. Our studies unveil a previously unrecognized progressive enhancer landscape where structurally equivalent components serve unique and differentiation-specific functions.
乳腺腔系细胞依赖于常见的细胞因子感应转录因子 STAT5 在怀孕时建立超级增强子，并启动一个激活乳汁生成的遗传程序。随着幼崽的成长，对乳汁的巨大需求要求乳腺细胞在泌乳过程中进行渐进式分化。在这里，我们研究了哺乳期持续的激素暴露如何塑造不断发展的增强子景观，并影响乳腺细胞的生物学。通过 ChIP-seq，我们发现乳腺增强子上转录因子占据的位置发生了变化，这表明它们的活性随着分化的推进而演变。利用小鼠遗传学，我们证明了 Wap 超级增强子内单个增强子的功能随着泌乳的进展而进化。最显著的是，一个种子增强子，它在怀孕期间激活 Wap 超级增强子是必需的，但在哺乳期则不需要，这表明存在补偿性的灵活性。结构上等同的组成增强子的组合缺失表明在哺乳期具有分化特异性的补偿活性。我们还证明，Wap 超级增强子是由 STAT5 和其他常见转录因子构建的，当它被放置在全局允许的染色质中时，仍然保持其乳腺特异性，这表明染色质在控制细胞特异性方面的作用有限。我们的研究揭示了一个以前未被认识的渐进性增强子景观，其中结构上等同的成分具有独特的和分化特异性的功能。
