The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors.
The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors.
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DOI：
10.1016/j.stem.2015.08.007
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发表时间：
2015-09-03
期刊：
影响因子：
23.9
通讯作者：
Dobreva G
中科院分区：
文献类型：
--
作者：
Caputo L;Witzel HR;Kolovos P;Cheedipudi S;Looso M;Mylona A;van IJcken WF;Laugwitz KL;Evans SM;Braun T;Soler E;Grosveld F;Dobreva G
心脏干/祖细胞具有巨大的再生治疗潜力，然而，调节其扩增和分化的机制仍然没有充分的定义。在这里，我们表明，Ldb 1是心脏祖细胞基因组组织的中央调节器，这是心脏谱系分化和心脏发育的关键。我们证明，Ldb 1结合到心脏祖细胞的关键调节器，Isl 1，并保护它免受降解。此外，Isl 1/Ldb 1复合物在核心心脏转录因子Mef 2c和Hand 2的位点促进长距离增强子-启动子相互作用。染色体构象捕获后测序鉴定了Isl 1/Ldb 1响应性Mef 2c前心野增强子与在心脏祖细胞功能和心血管发育中起关键作用的基因的特异性Ldb 1介导的相互作用。重要的是，这些基因的表达下调Ldb 1耗尽和Isl 1/Ldb 1单倍缺陷。总之，Isl 1/Ldb 1复合体在心脏发生过程中协调了心脏特异性转录调控和三维空间协调的网络。Caputo等人将Ldb 1鉴定为心脏发生的关键调节因子。Ldb 1结合关键的心脏转录因子Isl 1并保护其免于降解。稳定的Isl 1/Ldb 1复合物在三维空间中协调转录调控和协调网络，驱动心脏祖细胞分化和心脏发育。
Cardiac stem/progenitor cells hold great potential for regenerative therapies; however, the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that Ldb1 is a central regulator of genome organization in cardiac progenitor cells, which is crucial for cardiac lineage differentiation and heart development. We demonstrate that Ldb1 binds to the key regulator of cardiac progenitors, Isl1, and protects it from degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range enhancer-promoter interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified specific Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field enhancer with genes that play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was downregulated upon Ldb1 depletion and Isl1/Ldb1 haplodeficiency. In conclusion, the Isl1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis. Caputo et al. identify Ldb1 as a crucial regulator of cardiogenesis. Ldb1 binds the key cardiac transcription factor Isl1 and protects it from degradation. The stabilized Isl1/Ldb1 complex orchestrates a network for transcriptional regulation and coordination in three-dimensional space, driving cardiac progenitor cell differentiation and heart development.
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影响因子：
64.8
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