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首页> 外文期刊>Epigenetics & Chromatin >Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation
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Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation

机译：染色质重塑酶Brg1是小鼠晶状体纤维细胞末端分化和脱核所必需的

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Background Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2β) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific αA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase IIβ, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase IIβ, for lens fiber cell denucleation and indirectly for retinal development. Conclusions These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase IIβ as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.
机译：背景梵天相关基因1（Brg1，也称为Smarca4和Snf2β）编码（开关/蔗糖不可发酵）（SWI / SNF）染色质重塑复合物的5'-三磷酸腺苷（ATP）依赖的催化亚基。 SWI / SNF复合物通过多种机制募集到染色质，包括特定的DNA结合因子（例如，热激转录因子4（Hsf4）和配对盒基因6（Pax6）），染色质结构蛋白（例如，高迁移率） A1组（HMGA1））和/或乙酰化核心组蛋白。先前的研究表明，Brg1 ATPase域中的单个氨基酸取代（K798R）通过显性负（dn）机制起作用。遗传研究表明，Brg1是早期（即植入前）小鼠胚胎发育的必需基因。 Brg1还控制神经干细胞的维持，多种细胞谱系和器官（包括T细胞，神经胶质细胞和四肢）的终末分化。结果为了检查Brg1在小鼠晶状体发育中的作用，使用有晶状体特异性αA-crystallin启动子在有丝分裂后晶状体纤维细胞中表达了dnBrg1转基因构建体。形态学研究表明转基因晶状体中异常的晶状体纤维细胞分化导致白内障。电子显微镜研究显示晶状体缝线形成异常和晶状体纤维细胞的溶核作用不完全（即去核）。为了鉴定由Brg1调控的基因，在胚胎第15.5天（E15.5）野生型和dnBrg1转基因晶状体中进行RNA表达谱分析。此外，在dnBrg1转基因，Pax6杂合和Hsf4纯合透镜中差异表达的基因之间的比较确定了由Brg1，Hsf4和Pax6整合的多个基因。发现在每个Pax6，Brg1和Hsf4模型系统中，DNaseIIβ（晶状体纤维细胞脱核所需的关键酶）均被下调。使用条件基因靶向对Brg1进行晶状体特异性缺失显示，Brg1是晶状体纤维细胞分化，DNaseIIβ表达，晶状体纤维细胞去核和间接视网膜发育所必需的。结论这些研究证明了Brg1在晶状体纤维细胞末端分化中的细胞自主作用，并将DNaseIIβ鉴定为SWI / SNF复合物的潜在直接靶标。 Brg1直接或间接参与降解晶状体纤维细胞染色质的过程。原子核和其他细胞器的存在产生的散射光与晶状体的光学要求不符。

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