Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
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DOI：
10.1172/jci.insight.156046
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发表时间：
2022-02-02
期刊：
影响因子：
8
通讯作者：
Mani A
中科院分区：
文献类型：
--
作者：
Hong L;Li N;Gasque V;Mehta S;Ye L;Wu Y;Li J;Gewies A;Ruland J;Hirschi KK;Eichmann A;Hendry C;van Dijk D;Mani A
驱动获得不同的神经嵴细胞（NCC）命运的分子机制仍然知之甚少。在这里，我们确定Prdm 6作为一种表观遗传修饰剂，在时间和空间上调节NCC指定符的表达，并决定迁移性心脏NCC（CNCC）的一个子集的命运。在转基因小鼠中使用转录组学分析和遗传和命运作图方法，我们发现Prdm 6的破坏与CNCC分化受损、分层和迁移相关，并导致动脉导管未闭（DA）和心室致密化不全。DA和CNCC的批量和单细胞RNA-Seq分析确定Prdm 6是CNCC特化基因网络的调节因子，包括Wnt 1，Tfap 2b和Sox 9。CNCC中Prdm 6的缺失减少了其在前上皮间质转化（pre-EMT）簇中的表达，导致NCC在背神经管中的保留。这种缺陷与减少H4 K20单甲基化和G1-S进展以及EMT前和神经管簇中Wnt 1转录水平增加有关，我们发现这是CNCC迁移受损的主要驱动因素。总之，这些发现揭示了Prdm 6是CNCC分化和迁移的关键调节因子，并将Prdm 6及其调节网络确定为治疗先天性心脏病的潜在靶点。
The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs). Using transcriptomic analysis and genetic and fate mapping approaches in transgenic mice, we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction. Bulk and single-cell RNA-Seq analyses of the DA and CNCCs identified Prdm6 as a regulator of a network of CNCC specification genes, including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial–mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube. This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration. Altogether, these findings revealed Prdm6 as a key regulator of CNCC differentiation and migration and identified Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.
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影响因子：
3.8
作者：
Laufer, Benjamin I.;Kapalanga, Joachim;Singh, Shiva M.
通讯作者：
Singh, Shiva M.
影响因子：
3.7
作者：
Chater-Diehl EJ;Laufer BI;Castellani CA;Alberry BL;Singh SM
通讯作者：
Singh SM
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
2.7
作者：
BOUDREAU, N;TURLEY, E;RABINOVITCH, M
通讯作者：
RABINOVITCH, M
DOI：
10.1083/jcb.200411095
发表时间：
2005-04-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kléber M;Lee HY;Wurdak H;Buchstaller J;Riccomagno MM;Ittner LM;Suter U;Epstein DJ;Sommer L
通讯作者：
Sommer L