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BRD9在胎儿造血过程中的深入功能分析揭示了其依赖于背景的作用。

In-depth functional analysis of BRD9 in fetal hematopoiesis reveals context-dependent roles.

作者信息

Zhang Yifan, Nomura Masaki, Nishimura Koutarou, Zang Weijia, Koike Yui, Xiao Muran, Ito Hiromi, Fukumoto Miki, Tanaka Atsushi, Aoyama Yumi, Saika Wataru, Hasegawa Chihiro, Yamazaki Hiromi, Takaori-Kondo Akifumi, Inoue Daichi

机构信息

Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.

Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

iScience. 2025 Feb 12;28(3):112010. doi: 10.1016/j.isci.2025.112010. eCollection 2025 Mar 21.

DOI:10.1016/j.isci.2025.112010
PMID:40109374
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11919606/
Abstract

The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analysis, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.

摘要

调控成体造血的造血干细胞（HSC）的层级组织已得到广泛研究。然而，从胎儿造血到成体造血的动态表观基因组转变仍未被完全理解，尤其是关于表观遗传因子的参与情况。在本研究中，我们探究了BRD9在胎儿造血中的作用，BRD9是非经典BAF（ncBAF）复合物的一个重要组成部分，已知其调控成体HSC的命运。与在成体造血中的观察结果一致，BRD9缺失会损害胎儿HSC的干性并扰乱红系成熟。有趣的是，对髓系谱系的影响存在差异：在胎儿模型和成人模型中，BRD9缺失分别抑制和促进了髓系分化。通过全面的转录组和表观基因组分析，我们以背景和谱系依赖的方式阐明了BRD9的不同作用。我们的数据揭示了BRD9/ncBAF复合物如何以阶段特异性方式调节转录，为从胎儿造血到成体造血转变背后的表观遗传调控提供了更深入的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/ff25453217a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/e4d8a602a524/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/7caecfc321cf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/c22e49634279/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/701ed3e7d2f6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/0609721d87ac/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/86822c2f6551/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/ff25453217a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/e4d8a602a524/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/7caecfc321cf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/c22e49634279/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/701ed3e7d2f6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/0609721d87ac/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/86822c2f6551/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d0/11919606/ff25453217a2/gr6.jpg

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本文引用的文献

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Nat Commun. 2023 Dec 15;14(1):8372. doi: 10.1038/s41467-023-44081-6.
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Dictionary learning for integrative, multimodal and scalable single-cell analysis.基于字典学习的综合、多模态和可扩展的单细胞分析。
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A Refined Single Cell Landscape of Haematopoiesis in the Mouse Foetal Liver.小鼠胎儿肝脏造血作用的精细单细胞图谱
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A relay velocity model infers cell-dependent RNA velocity.接力速度模型推断细胞依赖的 RNA 速度。
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Temporal multimodal single-cell profiling of native hematopoiesis illuminates altered differentiation trajectories with age.对天然造血进行时空调控的单细胞分析揭示了随年龄变化的分化轨迹。
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