Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
PLoS One. 2012;7(8):e43300. doi: 10.1371/journal.pone.0043300. Epub 2012 Aug 28.
Product of the Itga2b gene, CD41 contributes to hematopoietic stem cell (HSC) and megakaryocyte/platelet functions. CD41 expression marks the onset of definitive hematopoiesis in the embryo where it participates in regulating the numbers of multipotential progenitors. Key to platelet aggregation, CD41 expression also characterises their precursor, the megakaryocyte, and is specifically up regulated during megakaryopoiesis. Though phenotypically unique, megakaryocytes and HSC share numerous features, including key transcription factors, which could indicate common sub-regulatory networks. In these respects, Itga2b can serve as a paradigm to study features of both developmental-stage and HSC- versus megakaryocyte-specific regulations. By comparing different cellular contexts, we highlight a mechanism by which internal promoters participate in Itga2b regulation. A developmental process connects epigenetic regulation and promoter switching leading to CD41 expression in HSC. Interestingly, a similar process can be observed at the Mpl locus, which codes for another receptor that defines both HSC and megakaryocyte identities. Our study shows that Itga2b expression is controlled by lineage-specific networks and associates with H4K8ac in megakaryocyte or H3K27me3 in the multipotential hematopoietic cell line HPC7. Correlating with the decrease in H3K27me3 at the Itga2b Iocus, we find that following commitment to megakaryocyte differentiation, the H3K27 demethylase Jmjd3 up-regulation influences both Itga2b and Mpl expression.
Itga2b 基因的产物 CD41 有助于造血干细胞 (HSC) 和巨核细胞/血小板功能。CD41 的表达标志着胚胎中定型造血的开始，它参与调节多能祖细胞的数量。作为血小板聚集的关键，CD41 的表达也标记着其前体细胞巨核细胞，并在巨核细胞生成过程中特异性上调。尽管巨核细胞和 HSC 在表型上是独特的，但它们具有许多共同的特征，包括关键转录因子，这表明它们可能存在共同的调控网络。在这些方面，Itga2b 可以作为研究发育阶段和 HSC 与巨核细胞特异性调控特征的范例。通过比较不同的细胞环境，我们强调了内部启动子参与 Itga2b 调控的一种机制。一个发育过程将表观遗传调控和启动子切换连接起来，导致 HSC 中 CD41 的表达。有趣的是，类似的过程也可以在编码另一个受体的 Mpl 基因座中观察到，该受体定义了 HSC 和巨核细胞的身份。我们的研究表明，Itga2b 的表达受谱系特异性网络的控制，并与巨核细胞中的 H4K8ac 或多潜能造血细胞系 HPC7 中的 H3K27me3 相关联。与 Itga2b 基因座上 H3K27me3 的减少相关，我们发现，在向巨核细胞分化的过程中，H3K27 去甲基化酶 Jmjd3 的上调会影响 Itga2b 和 Mpl 的表达。
