Chemotherapy suppresses SHH gene expression via a specific enhancer

Sonic hedgehog(SHH)signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal(GI)cancer progression.Regulation of SHH gene expression is a paradigm of long-range enhancer function.Using the classical chemotherapy drug 5-fluorouracil(5FU)as an example,here we show that SHH gene expression is suppressed by chemotherapy.SHH is downstream of immediate early genes(IEGs),including Early growth response 1(Egr1).A specific 139 kb upstream enhancer is responsible for its down-regulation.Knocking down EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy.We further demonstrate that down-regulation of SHH expression does not depend on 5FU’s impact on nucleotide metabolism or DNA damage;rather,a sustained oxidative stress response mediates this rapid suppression.This enhancer is present in a wide range of tumors and normal tissues,thus providing a target for cancer chemotherapy and its adverse effects on normal tissues.We propose that SHH is a stress-responsive gene downstream of IEGs,and that traditional chemotherapy targets a specific enhancer to suppress its expression.

濒危植物百山祖冷杉种子发育特征及其胚培养

百山祖冷杉(Abies beshanzuensis)种子萌发率低,发育特性尚不明确,极大地限制了种群在原生境的自然更新。该研究以百山祖冷杉不同发育时期的雌球果为材料,通过研究球果中种子的胚与胚乳数量、重量和显微结构特性,及测定种子发育关键时期胚乳的初生代谢物,探究种子发育特征及影响种子发育的主要因素。结果表明, 7月是百山祖冷杉种子发育的关键时期,此期间胚乳重量快速增加,胚乳中碳水化合物代谢活动旺盛。解剖学和形态学分析显示,7月下旬球果中大量种子发育异常。进一步对发育关键时期胚乳中初生代谢物进行分析表明,海藻糖-6-磷酸含量显著降低。推测在种子发育的关键时期胚乳中海藻糖-6-磷酸降低可能是种子发育异常的重要原因之一。基于种子发育特征,该研究建立了百山祖冷杉未成熟胚培养技术体系,并成功获得试管苗。