Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells
Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells
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DOI：
10.1111/j.1349-7006.2011.02159.x
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发表时间：
2012-03
期刊：
影响因子：
5.7
通讯作者：
Yang Xi;Sugiko Watanabe;Yuko Hino;Chiyomi Sakamoto;Y. Nakatsu;S. Okada;M. Nakao
中科院分区：
文献类型：
--
作者：
Yang Xi;Sugiko Watanabe;Yuko Hino;Chiyomi Sakamoto;Y. Nakatsu;S. Okada;M. Nakao
高迁移率族A1（Hmga 1）蛋白是一种结构性染色质因子，小鼠中Hmga 1的异常表达可导致造血系统恶性肿瘤伴细胞分化缺陷。然而，Hmga 1在造血发育和白血病细胞中的功能参与仍有待阐明。使用内源性表达Hmga 1-GFP融合蛋白的Hmga 1-绿色荧光蛋白（GFP）敲入小鼠，我们检测了Hmga 1在未分化和分化的造血细胞群体中的表达。在胸腺早期T细胞发育过程中，Hmga 1在CD 4/CD 8-双阴性（DN）细胞中高度表达，在CD 4/CD 8-双阳性（DP）细胞中短暂下调。因此，Hmga 1直接结合DN期细胞中CD 4/CD 8基因座和异染色质病灶中的顺式调节元件，但不结合DP细胞。有趣的是，DN期白血病细胞中的CD 4/CD 8表达是通过抑制Hmga 1与核DNA的结合或RNA干扰介导的Hmga 1敲低来诱导的。此外，Hmga 1耗尽的白血病T细胞显着减少增殖，细胞周期蛋白依赖性激酶抑制剂基因的转录激活作为Hmga 1的直接靶点。本研究中的数据揭示了Hmga 1在T细胞谱系和白血病细胞中的转录沉默中的作用。（Cancer Sci 2012; 103：439-447）
High‐mobility group A1 (Hmga1) protein is an architectural chromatin factor, and aberrant Hmga1 expression in mice causes hematopoietic malignancies with defects in cellular differentiation. However, the functional involvement of Hmga1 in hematopoietic development and leukemic cells remains to be elucidated. Using Hmga1‐green fluorescent protein (GFP) knock‐in mice that endogenously express an Hmga1‐GFP fusion protein, we examined Hmga1 expression in undifferentiated and differentiated populations of hematopoietic cells. During early T cell development in the thymus, Hmga1 is highly expressed in CD4/CD8‐double negative (DN) cells and is transiently downregulated in CD4/CD8‐double positive (DP) cells. Consistently, Hmga1 directly binds to cis‐regulatory elements in the CD4/CD8 loci and the heterochromatin foci in DN‐stage cells, but not in DP cells. Interestingly, CD4/CD8 expression in DN‐stage leukemic cells is induced by inhibition of Hmga1 binding to nuclear DNA or RNA interference‐mediated Hmga1 knockdown. In addition, Hmga1‐depleted leukemic T cells markedly diminish proliferation, with transcriptional activation of cyclin‐dependent kinase inhibitor genes as a direct target of Hmga1. The data in the present study reveal a role of Hmga1 in transcriptional silencing in T cell lineages and leukemic cells. (Cancer Sci 2012; 103: 439–447)