The acidic domain of Hmga2 and the domain’s linker region are critical for driving self-renewal of hematopoietic stem cell
The acidic domain of Hmga2 and the domain’s linker region are critical for driving self-renewal of hematopoietic stem cell
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DOI：
10.1007/s12185-021-03274-9
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发表时间：
2022-01
影响因子：
2.1
通讯作者：
Yuqi Sun;Sho Kubota;Mihoko Iimori;Ai Hamashima;H. Murakami;J. Bai;Mariko Morii;Takako Yokomizo-Nakano;Motomi Osato;K. Araki;G. Sashida
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文献类型：
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作者：
Yuqi Sun;Sho Kubota;Mihoko Iimori;Ai Hamashima;H. Murakami;J. Bai;Mariko Morii;Takako Yokomizo-Nakano;Motomi Osato;K. Araki;G. Sashida
高迁移率族AT-钩2（Hmga 2）是一种染色质修饰蛋白，其通过其AT-钩结构域与染色质和DNA结合，在胎儿发育和白血病传播中起关键作用。然而，Hmga 2激活靶基因表达以驱动造血干细胞（HSC）自我更新的分子机制仍不清楚。我们建立了Rosa 26位点Hmga 2条件性基因敲入小鼠，发现Hmga 2的过表达促进了正常HSC的自我更新，但维持了它们在骨髓中的适应性，因此不足以引发恶性肿瘤。这一结果与Hmga 2是原癌基因的研究结果一致。我们还评估了缺乏功能结构域的Hmga 2突变体的细胞功能，并证明了Hmga 2的C-末端酸性结构域和该结构域的连接区对于激活干细胞特征相关基因（如Igf 2bp 2基因）以驱动HSC增殖至关重要。相反，Hmga 1（Hmga家族中具有不同连接区的成员）的过表达并不驱动HSC的增殖。我们的研究结果揭示了Hmga 2的酸性结构域和该结构域的连接区在调节HSC的转录和自我更新功能中的关键作用。
High mobility group AT-hook 2 (Hmga2) is a chromatin modifier protein that plays a critical role in fetal development and leukemia propagation by binding to chromatin and DNA via its AT-hook domains. However, the molecular mechanisms by which Hmga2 activates the expression of target genes to drive the self-renewal of hematopoietic stem cells (HSCs) remain unclear. We generatedRosa26locusHmga2conditional knock-in mice and found that overexpression ofHmga2promoted self-renewal of normal HSCs, but maintained their fitness in bone marrow, and consequently was not sufficient to initiate malignancy. This result is consistent with previous findings showing thatHmga2is a proto-oncogene. We also assessed the cellular functions ofHmga2mutants lacking functional domains and demonstrated that the C-terminus acidic domain of Hmga2 and the domain’s linker region were critical for activating genes involved in stem cell signatures, such as theIgf2bp2gene, to drive proliferation of HSCs. In contrast, overexpression ofHmga1, a member of the Hmga family with a different linker region, did not drive proliferation of HSCs. Our results reveal a critical role for the acidic domain of Hmga2 and the domain’s linker region in modulating the transcription and self-renewal functions of HSCs.