Org Tõnis, Duan Dan, Ferrari Roberto, Montel-Hagen Amelie, Van Handel Ben, Kerényi Marc A, Sasidharan Rajkumar, Rubbi Liudmilla, Fujiwara Yuko, Pellegrini Matteo, Orkin Stuart H, Kurdistani Siavash K, Mikkola Hanna Ka
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
Department of Biological Chemistry, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA.
EMBO J. 2015 Mar 12;34(6):759-77. doi: 10.15252/embj.201490542. Epub 2015 Jan 6.
Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated.
Scl/Tal1通过未知机制赋予胚胎内皮细胞造血能力并防止异位心肌生成。我们发现，Scl与造血和心脏增强子结合，这些增强子在多能心血管中胚层中发生表观遗传预激活，以调节造血和心脏谱系的分化。Scl并非作为先驱因子发挥作用，而是利用预先建立的表观遗传格局。随着血液谱系的出现，Scl结合和活跃的表观遗传修饰在造血增强子中持续存在，而心脏增强子则通过去除活跃的表观遗传标记而失活。我们的数据表明，Scl并非通过招募共抑制因子至增强子来防止异位心脏生成，而是通过占据诸如Gata4和Hand1等心脏因子用于基因激活的增强子来实现。尽管造血Gata因子与Scl结合于激活和抑制的基因，但它们对于心脏抑制是可有可无的，但对于激活促进造血干/祖细胞发育的基因是必需的。这些结果表明，在命运决定时期，谱系特异性基因中可被相反命运调节因子作用的独特增强子子集提供了一个协调互斥命运分化的平台。
