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造血祖细胞基因组的双重炎症感知机制

Dual mechanism of inflammation sensing by the hematopoietic progenitor genome.

作者信息

Tran Vu L, Liu Peng, Katsumura Koichi R, Soukup Alexandra A, Kopp Audrey, Ahmad Zamaan S, Mattina Ashley E, Brand Marjorie, Johnson Kirby D, Bresnick Emery H

机构信息

Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Department of Biostatistics and Biomedical Informatics, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

出版信息

Sci Adv. 2025 May 30;11(22):eadv3169. doi: 10.1126/sciadv.adv3169. Epub 2025 May 28.

DOI:10.1126/sciadv.adv3169
PMID:40435239
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12118549/
Abstract

Genomes adapt dynamically to alterations in the signaling milieu, including inflammation that transiently or permanently disrupts genome function. Here, we elucidate how a progenitor cell genome senses and responds to inflammation when the developmental and transcriptional regulator GATA2 is limiting, which causes bone marrow failure in humans and mice and predisposes to leukemia in humans. GATA2 murine progenitors are hypersensitive to inflammatory mediators. We discovered that the hematopoietic transcription factor PU.1 conferred transcriptional activation in GATA2 progenitors in response to Interferon-γ and Toll-Like Receptor 1/2 agonists. In a locus-specific manner, inflammation reconfigured genome activity by promoting PU.1 recruitment to chromatin or tuning activity of PU.1-preoccupied chromatin. The recruitment mechanism disproportionately required IKKβ activity. Inflammation-activated genes were enriched in motifs for RUNX factors that cooperate with GATA factors. Contrasting with the GATA2-RUNX1 cooperativity paradigm, GATA2 suppressed and RUNX1 promoted PU.1 mechanisms to endow the progenitor genome with inflammation-sensing capacity.

摘要

基因组会动态适应信号环境的变化，包括那些会暂时或永久破坏基因组功能的炎症。在此，我们阐明了当发育和转录调节因子GATA2受到限制时，祖细胞基因组如何感知并响应炎症，GATA2受限会导致人类和小鼠出现骨髓衰竭，并使人类易患白血病。GATA2小鼠祖细胞对炎症介质高度敏感。我们发现，造血转录因子PU.1在GATA2祖细胞中响应干扰素-γ和Toll样受体1/2激动剂时赋予转录激活作用。炎症以基因座特异性方式通过促进PU.1募集到染色质或调节PU.1占据的染色质的活性来重新配置基因组活性。募集机制特别需要IKKβ活性。炎症激活的基因富含与GATA因子协同作用的RUNX因子的基序。与GATA2-RUNX1协同作用模式相反，GATA2抑制而RUNX1促进PU.1机制，以使祖细胞基因组具备炎症感知能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9061/12118549/5248f82623c5/sciadv.adv3169-f9.jpg
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本文引用的文献

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The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling.转录因子 NF-κB 在 Toll 样受体 4 信号转导的初级反应中协调核小体重塑。
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