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IκBα 通过视黄酸在胚胎发育过程中控制造血干细胞的休眠。

IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development.

机构信息

Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.

Josep Carreras Leukemia Research Institute, Barcelona, Spain.

出版信息

Nat Commun. 2024 Jun 1;15(1):4673. doi: 10.1038/s41467-024-48854-5.

DOI:10.1038/s41467-024-48854-5
PMID:38824124
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11144194/
Abstract

Recent findings suggest that Hematopoietic Stem Cells (HSC) and progenitors arise simultaneously and independently of each other already in the embryonic aorta-gonad mesonephros region, but it is still unknown how their different features are established. Here, we uncover IκBα (Nfkbia, the inhibitor of NF-κB) as a critical regulator of HSC proliferation throughout development. IκBα balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of IκBα decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, IκBα deficient HSCs respond with superior activation to in vitro culture and in serial transplantation. At the molecular level, chromatin regions harboring binding motifs for retinoic acid signaling are hypo-methylated for the PRC2 dependent H3K27me3 mark in IκBα deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a IκBα-PRC2 axis, which controls retinoic acid signaling.

摘要

最近的研究结果表明，造血干细胞（HSC）和祖细胞在胚胎主动脉-性腺-中肾区同时且独立地产生，但它们的不同特征是如何建立的仍不清楚。在这里，我们发现 IκBα（Nfkbia，NF-κB 的抑制剂）是整个发育过程中 HSC 增殖的关键调节因子。IκBα与表观遗传沉默因子 PRC2 一起平衡视黄酸信号水平，特别是在 HSCs 中。IκBα 的缺失会降低 HSC 的增殖，并诱导休眠相关基因表达特征。此外，IκBα 缺陷的 HSCs 对体外培养和连续移植的反应更活跃。在分子水平上，在 IκBα 缺陷的 HSCs 中，含有视黄酸信号结合基序的染色质区域的 PRC2 依赖性 H3K27me3 标记物的甲基化程度较低。总的来说，我们表明，发育中的 HSCs 的增殖指数受 IκBα-PRC2 轴的调节，该轴控制视黄酸信号。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/03f4b6e75788/41467_2024_48854_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/024ed8800ad9/41467_2024_48854_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/1576834562ab/41467_2024_48854_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/81054790d427/41467_2024_48854_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/87c79a601dd6/41467_2024_48854_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/1b28c795936a/41467_2024_48854_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/03f4b6e75788/41467_2024_48854_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/024ed8800ad9/41467_2024_48854_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/1576834562ab/41467_2024_48854_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/81054790d427/41467_2024_48854_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/87c79a601dd6/41467_2024_48854_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/1b28c795936a/41467_2024_48854_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f401/11144194/03f4b6e75788/41467_2024_48854_Fig6_HTML.jpg

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