Cohesin mediates Esco2-dependent transcriptional regulation in a zebrafish regenerating fin model of Roberts Syndrome.
Cohesin mediates Esco2-dependent transcriptional regulation in a zebrafish regenerating fin model of Roberts Syndrome.
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DOI：
10.1242/bio.026013
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发表时间：
2017-12-15
期刊：
影响因子：
2.4
通讯作者：
Iovine MK
中科院分区：
文献类型：
--
作者：
Banerji R;Skibbens RV;Iovine MK
罗伯特综合征（RBS）和科尔内利亚德兰格综合征（CdLS）是以颅面畸形、肢体畸形和智力低下为特征的人类发育障碍。这些出生缺陷统称为粘着蛋白病，因为两者都是由粘着基因突变引起的。CdLS的产生是由于常染色体显性突变或粘附素亚基（SMC 1A、SMC 3和RAD 21）或粘附素辅助因子（NIPBL和HDAC 8）的单倍性，导致发育程序的转录失调。RBS的产生是由于粘附素辅助因子ESCO 2的常染色体隐性突变，ESCO 2是编码靶向粘附素复合物的SMC 3亚基的N-乙酰转移酶的基因。然而，RBS背后的机制仍然未知。一个流行的模型指出，RBS的产生是由于有丝分裂失败和祖细胞干细胞通过凋亡的损失。然而，先前在斑马鱼再生鳍中的发现表明，Esco 2敲低导致转录失调，独立于细胞凋亡，类似于在CdLS患者中观察到的。以前，我们使用临床相关的CX43来证明Esco 2的转录作用。CX43是所有脊椎动物中保守的间隙连接基因，其是相邻细胞之间直接细胞间通讯所需的，使得cx43突变导致眼齿趾发育不良。在这里，我们发现吗啉介导的smc 3敲低降低了cx43的表达，并扰乱了斑马鱼的骨骼和组织再生类似于先前报道的esco 2敲低。同样类似于Esco 2依赖的表型，Smc 3依赖的骨和组织再生缺陷被转基因Cx43过表达所拯救，这表明Smc 3和Esco 2协同作用以调节Cx43转录。为了支持这一模型，染色质免疫沉淀试验表明，Smc 3结合到cx43启动子的离散区域，表明Esco 2通过修饰Smc 3结合到cx43启动子来发挥cx43的转录调控。这些发现有可能将RBS和CdLS统一为基于转录的机制。总结：这项研究揭示了RBS的潜在机制，其中ESCO 2突变导致包括临床相关信号分子CX 43在内的转录程序的粘附素依赖性失调。这篇文章有一个相关的第一人称采访的第一作者的文件作为补充信息的一部分。
Robert syndrome (RBS) and Cornelia de Lange syndrome (CdLS) are human developmental disorders characterized by craniofacial deformities, limb malformation and mental retardation. These birth defects are collectively termed cohesinopathies as both arise from mutations in cohesion genes. CdLS arises due to autosomal dominant mutations or haploinsufficiencies in cohesin subunits (SMC1A, SMC3 and RAD21) or cohesin auxiliary factors (NIPBL and HDAC8) that result in transcriptional dysregulation of developmental programs. RBS arises due to autosomal recessive mutations in cohesin auxiliary factor ESCO2, the gene that encodes an N-acetyltransferase which targets the SMC3 subunit of the cohesin complex. The mechanism that underlies RBS, however, remains unknown. A popular model states that RBS arises due to mitotic failure and loss of progenitor stem cells through apoptosis. Previous findings in the zebrafish regenerating fin, however, suggest that Esco2-knockdown results in transcription dysregulation, independent of apoptosis, similar to that observed in CdLS patients. Previously, we used the clinically relevant CX43 to demonstrate a transcriptional role for Esco2. CX43 is a gap junction gene conserved among all vertebrates that is required for direct cell-cell communication between adjacent cells such that cx43 mutations result in oculodentodigital dysplasia. Here, we show that morpholino-mediated knockdown of smc3 reduces cx43 expression and perturbs zebrafish bone and tissue regeneration similar to those previously reported for esco2 knockdown. Also similar to Esco2-dependent phenotypes, Smc3-dependent bone and tissue regeneration defects are rescued by transgenic Cx43 overexpression, suggesting that Smc3 and Esco2 cooperatively act to regulate cx43 transcription. In support of this model, chromatin immunoprecipitation assays reveal that Smc3 binds to a discrete region of the cx43 promoter, suggesting that Esco2 exerts transcriptional regulation of cx43 through modification of Smc3 bound to the cx43 promoter. These findings have the potential to unify RBS and CdLS as transcription-based mechanisms. Summary: This study reveals an underlying mechanism of RBS in which ESCO2 mutation results in cohesin-dependent dysregulation of transcriptional programs that include the clinically relevant signaling molecule CX43. This article has an associated First Person interview with the first author of the paper as part of the supplementary information.
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