Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Medimmune, Granta Park, CB21 6GH, Cambridge, UK.
Nat Commun. 2018 Dec 18;9(1):5375. doi: 10.1038/s41467-018-07787-6.
During development, it is unclear if lineage-fated cells derive from multilineage-primed progenitors and whether active mechanisms operate to restrict cell fate. Here we investigate how mesoderm specifies into blood-fated cells. We document temporally restricted co-expression of blood (Scl/Tal1), cardiac (Mesp1) and paraxial (Tbx6) lineage-affiliated transcription factors in single cells, at the onset of blood specification, supporting the existence of common progenitors. At the same time-restricted stage, absence of SCL results in expansion of cardiac/paraxial cell populations and increased cardiac/paraxial gene expression, suggesting active suppression of alternative fates. Indeed, SCL normally activates expression of co-repressor ETO2 and Polycomb-PRC1 subunits (RYBP, PCGF5) and maintains levels of Polycomb-associated histone marks (H2AK119ub/H3K27me3). Genome-wide analyses reveal ETO2 and RYBP co-occupy most SCL target genes, including cardiac/paraxial loci. Reduction of Eto2 or Rybp expression mimics Scl-null cardiac phenotype. Therefore, SCL-mediated transcriptional repression prevents mis-specification of blood-fated cells, establishing active repression as central to fate determination processes.
在发育过程中，尚不清楚谱系定型细胞是否来自多谱系启动祖细胞，以及是否存在主动机制来限制细胞命运。在这里，我们研究中胚层如何特化为造血细胞。我们记录了血液（Scl/Tal1）、心脏（Mesp1）和轴旁（Tbx6）谱系相关转录因子在单个细胞中的时间限制共表达，在造血特化的起始时，支持共同祖细胞的存在。在同一时间限制阶段，SCL 的缺失导致心脏/轴旁细胞群体的扩张和心脏/轴旁基因表达的增加，表明对替代命运的主动抑制。事实上，SCL 通常激活共抑制因子 ETO2 和多梳蛋白-PRC1 亚基（RYBP、PCGF5）的表达，并维持多梳相关组蛋白标记（H2AK119ub/H3K27me3）的水平。全基因组分析显示，ETO2 和 RYBP 共同占据大多数 SCL 靶基因，包括心脏/轴旁基因座。减少 Eto2 或 Rybp 的表达可模拟 Scl 缺失的心脏表型。因此，SCL 介导的转录抑制可防止造血细胞的错误特化，确立主动抑制是命运决定过程的核心。
