作者
William T Ralvenius, Alison E Mungenast, Hannah Woolf, Margaret M Huston, Tyler Z Gillingham, Stephen K Godin, Jay Penney, Hugh P Cam, Fan Gao, Celia G Fernandez, Barbara Czako, Yaima Lightfoot, William J Ray, Adrian Beckmann, Alison M Goate, Edoardo Marcora, Carmen Romero-Molina, Pinar Ayata, Anne Schaefer, Elizabeta Gjoneska, Li-Huei Tsai
发表日期
2023/8/29
期刊
Journal of Experimental Medicine
卷号
220
期号
11
页码范围
e20222105
出版商
Rockefeller University Press
简介
Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer’s disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse …
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