The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Integrated Program in Cellular, Molecular, and Biomedical Studies, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Sci Adv. 2023 Mar 3;9(9):eadd2671. doi: 10.1126/sciadv.add2671.
Gene expression is changed by disease, but how these molecular responses arise and contribute to pathophysiology remains less understood. We discover that β-amyloid, a trigger of Alzheimer's disease (AD), promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. Through a multilevel approach based on AD datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors (ChIPmera), we find that CREB3L2-ATF4 activates a transcription network that interacts with roughly half of the genes differentially expressed in AD, including subsets associated with β-amyloid and tau neuropathologies. CREB3L2-ATF4 activation drives tau hyperphosphorylation and secretion in neurons, in addition to misregulating the retromer, an endosomal complex linked to AD pathogenesis. We further provide evidence for increased heterodimer signaling in AD brain and identify dovitinib as a candidate molecule for normalizing β-amyloid-mediated transcriptional responses. The findings overall reveal differential transcription factor dimerization as a mechanism linking disease stimuli to the development of pathogenic cellular states.
基因表达会受到疾病的影响，但这些分子反应是如何产生的，以及它们如何导致病理生理学变化，目前人们对此了解较少。我们发现β-淀粉样蛋白（一种阿尔茨海默病的诱因）会促进神经元中病理性 CREB3L2-ATF4 转录因子异二聚体的形成。通过基于 AD 数据集的多层次方法和一种新的化学遗传学方法（ChIPmera，可解析二聚体转录因子的基因组结合图谱），我们发现 CREB3L2-ATF4 会激活一个转录网络，该网络与 AD 中差异表达的大约一半基因相互作用，包括与β-淀粉样蛋白和 tau 神经病理学相关的亚群。CREB3L2-ATF4 的激活会导致神经元中的 tau 过度磷酸化和分泌，此外还会导致逆向转运体（与 AD 发病机制相关的内体复合物）失调。我们进一步提供了 AD 大脑中异二聚体信号增加的证据，并确定多韦替尼是一种可用于调节β-淀粉样蛋白介导的转录反应的候选分子。总的来说，这些发现揭示了差异转录因子二聚化作为一种将疾病刺激与致病细胞状态的发展联系起来的机制。
