Cornelia de Lange综合征相关因子NIPBL与BRD4 ET结构域相互作用，以控制一组共同基因的转录。,Cell Death & Disease

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Cornelia de Lange综合征相关因子NIPBL与BRD4 ET结构域相互作用，以控制一组共同基因的转录。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-07-18 , DOI: 10.1038/s41419-019-1792-x
Noelia Luna-Peláez ₁ , Rosana March-Díaz ₁ , María Ceballos-Chávez ₁ , Jose A Guerrero-Martínez ₁ , Paolo Grazioli ₂ , Pablo García-Gutiérrez ₁ , Thomas Vaccari ₃ , Valentina Massa ₂ , Jose C Reyes ₁ , Mario García-Domínguez ₁

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NIPBL中的突变是Cornelia de Lange综合征（CdLS）的主要原因。NIPBL是黏附素负载因子，最近已与BET（溴结构域和末端外（ET）结构域）蛋白BRD2和BRD4相关联。与此相关，已经描述了与BRD4突变相关的CdLS样表型。在这里，我们显示了NIPBL与酵母中不同BET成员的直接相互作用，以及与细胞中BRD4的选择性相互作用，这是参与相互作用的ET域。为了了解NIPBL和BET蛋白之间的关系，我们在耗尽不同蛋白后进行了RNA-Seq表达分析。结果表明，由NIPBL调控的基因与BRD4调控的基因大部分重叠，但与BRD2调控的基因没有重叠。ChIP-Seq分析表明，启动子优先占据NIPBL，击倒实验表明，NIPBL和BRD4在共同调控的启动子上相互稳定。此外，来自CdLS先证者的人成纤维细胞在NIPBL中发生突变，在共同占据的启动子处显示出BRD4减少。体内功能分析，使用果蝇果蝇的突变体，证实了Nipped-B和fs（1）h（分别为人类NIPBL和BRD4的直系同源物）之间的遗传相互作用。因此，我们为NIPBL和BRD4在转录调控中的合作提供了证据，这应该有助于解释最近观察到的与BRD4突变相关的CdLS样表型。使用果蝇果蝇的突变体，证实了Nipped-B和fs（1）h之间的遗传相互作用，fs（1）h是人类NIPBL和BRD4的直系同源物。因此，我们为NIPBL和BRD4在转录调控中的合作提供了证据，这应该有助于解释最近观察到的与BRD4突变相关的CdLS样表型。使用果蝇果蝇的突变体，证实了Nipped-B和fs（1）h之间的遗传相互作用，fs（1）h是人类NIPBL和BRD4的直系同源物。因此，我们为NIPBL和BRD4在转录调控中的合作提供了证据，这应该有助于解释最近观察到的与BRD4突变相关的CdLS样表型。

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The Cornelia de Lange Syndrome-associated factor NIPBL interacts with BRD4 ET domain for transcription control of a common set of genes.

Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin-loading factor and has recently been associated with the BET (bromodomains and extra-terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. Here, we show direct interaction of NIPBL with different BET members in yeast, and selective interaction with BRD4 in cells, being the ET domain involved in the interaction. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2. ChIP-Seq analysis indicates preferential NIPBL occupancy at promoters, and knockdown experiments show mutual stabilization of NIPBL and BRD4 on co-regulated promoters. Moreover, human fibroblasts from CdLS probands with mutations in NIPBL show reduced BRD4 at co-occupied promoters. Functional analysis in vivo, using mutants of Drosophila melanogaster, confirmed the genetic interaction between Nipped-B and fs(1)h, the orthologs of human NIPBL and BRD4, respectively. Thus, we provide evidence for NIPBL and BRD4 cooperation in transcriptional regulation, which should contribute to explain the recently observed CdLS-like phenotype associated with BRD4 mutations.

更新日期：2019-07-18

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