HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development.
HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development.
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HoxBlinc RNA 招募 Set1/MLL 复合物来激活 Hox 基因表达模式和中胚层谱系发育。
DOI：
10.1016/j.celrep.2015.12.007
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发表时间：
2016-01-05
期刊：
影响因子：
8.8
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Deng C;Li Y;Zhou L;Cho J;Patel B;Terada N;Li Y;Bungert J;Qiu Y;Huang S
三胸蛋白和长基因间非编码rna是胚胎干细胞多能性的关键调控因子；然而，它们是如何协同调节胚层中胚层规范的仍然是一个谜。我们在这里报道HoxBlinc RNA首先指定Flk1+中胚层，然后通过调节hoxb基因通路促进造血分化。HoxBlinc结合hoxb基因，招募Setd1a/MLL1复合物，并介导远程染色质相互作用以激活hoxb基因的转录。shrna介导的KD或crispr - cas9介导的基因缺失会抑制hoxb基因和其他调节心脏/造血分化的因子的表达。hoxb基因表达的减少伴随着Set1/MLL1和H3K4me3修饰募集的减少，以及染色质环形成的减少。hoxb2-b4基因在hoxblinc缺失的胚状体中重新表达，可以挽救经历造血分化的Flk1+前体。因此，HoxBlinc在控制hoxb转录网络中发挥重要作用，介导中胚层来源的Flk1+前体的规范和Flk1+细胞向造血谱系的分化。
Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1+ mesoderm and then promotes hematopoietic differentiation through regulating hoxb gene pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated KD or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb gene expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1+ precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1+ precursors and differentiation of Flk1+ cells into hematopoietic lineages.