Albert Mareike, Schmitz Sandra U, Kooistra Susanne M, Malatesta Martina, Morales Torres Cristina, Rekling Jens C, Johansen Jens V, Abarrategui Iratxe, Helin Kristian
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
PLoS Genet. 2013 Apr;9(4):e1003461. doi: 10.1371/journal.pgen.1003461. Epub 2013 Apr 18.
Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications.
胚胎发育受到转录因子和染色质相关蛋白的严格调控。H3K4me3与活跃转录相关，H3K27me3与基因抑制相关，而两者的组合使发育所需基因处于可塑性状态。在此我们表明，H3K4me2/3组蛋白去甲基化酶Jarid1b（Kdm5b/Plu1）的缺失会导致因呼吸衰竭引起的严重新生儿致死率。Jarid1b基因敲除胚胎有多种神经缺陷，包括颅神经紊乱、眼睛发育缺陷以及无脑畸形发生率增加。此外，鉴于Jarid1b和多梳蛋白靶基因存在重叠，Jarid1b基因敲除胚胎表现出多梳蛋白突变体典型的同源异型骨骼转化，这支持了多梳蛋白与Jarid1b之间存在功能相互作用。为了解Jarid1b如何调控小鼠发育，我们对组蛋白修饰进行了全基因组分析，结果表明，在Jarid1b基因敲除胚胎的早期胚胎发育过程中，编码发育调节因子的正常沉默基因会异常获得H3K4me3。随着胚胎发育的进行，H3K4me3不断积累，导致Jarid1b基因敲除小鼠大脑中神经主调节因子如Pax6和Otx2的表达增加。综上所述，这些结果表明，Jarid1b通过保护发育基因避免不适当获得活跃组蛋白修饰来调控小鼠发育。
