Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Gran Via de L'Hospitalet, 199-203, Hospitalet de Llobregat, Barcelona 08908, Spain; Center for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain.
Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Universitat Pompeu Fabra, Barcelona 08003, Spain.
Stem Cell Reports. 2019 Sep 10;13(3):515-529. doi: 10.1016/j.stemcr.2019.07.009. Epub 2019 Aug 8.
In vertebrates, GATA2 is a master regulator of hematopoiesis and is expressed throughout embryo development and in adult life. Although the essential role of GATA2 in mouse hematopoiesis is well established, its involvement during early human hematopoietic development is not clear. By combining time-controlled overexpression of GATA2 with genetic knockout experiments, we found that GATA2, at the mesoderm specification stage, promotes the generation of hemogenic endothelial progenitors and their further differentiation to hematopoietic progenitor cells, and negatively regulates cardiac differentiation. Surprisingly, genome-wide transcriptional and chromatin immunoprecipitation analysis showed that GATA2 bound to regulatory regions, and repressed the expression of cardiac development-related genes. Moreover, genes important for hematopoietic differentiation were upregulated by GATA2 in a mostly indirect manner. Collectively, our data reveal a hitherto unrecognized role of GATA2 as a repressor of cardiac fates, and highlight the importance of coordinating the specification and repression of alternative cell fates.
在脊椎动物中，GATA2 是造血的主要调节因子，在胚胎发育和成年期都有表达。尽管 GATA2 在小鼠造血中的基本作用已得到充分证实，但它在人类早期造血发育中的作用尚不清楚。通过结合时间控制的 GATA2 过表达与基因敲除实验，我们发现 GATA2 在中胚层特化阶段促进了造血内皮祖细胞的生成及其向造血祖细胞的进一步分化，并负调控心脏分化。令人惊讶的是，全基因组转录组和染色质免疫沉淀分析表明，GATA2 结合到调节区域，并抑制心脏发育相关基因的表达。此外，GATA2 以一种主要是间接的方式上调了对造血分化很重要的基因。总之，我们的数据揭示了 GATA2 作为心脏命运抑制因子的一个以前未被认识的作用，并强调了协调替代细胞命运的特化和抑制的重要性。
