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首页> 外文期刊>Nucleus >Chromatin changes in SMARCAL1 deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia
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Chromatin changes in SMARCAL1 deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia

机译：SMARCAL1缺乏症中的染色质变化：Schimke免疫性骨发育不良的基因表达改变的假说

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摘要

Mutations in SMARCAL1, which encodes a DNA annealing helicase with roles in DNA replication fork restart, DNA repair, and gene expression modulation, cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive disease characterized by skeletal dysplasia, renal disease, T-cell immunodeficiency, and arteriosclerosis. The clinical features of SIOD arise from pathological changes in gene expression; however, the underlying mechanism for these gene expression alterations remains unclear. We hypothesized that changes of the epigenome alter gene expression in SIOD. To test this, we performed a genetic screen for interaction between Marcal1, the Drosophila melanogaster ortholog of SMARCAL1, and the genes of the trithorax group (trxG) and Polycomb group (PcG), which encode epigenetic regulators. SMARCAL1 and Marcal1 genetically interacted with trxG and PcG members. A homozygous null mutation of Marcal1 suppressed the wing-to-haltere transformation, ectopic Ultrabithorax (Ubx) expression, and ectopic Ubx minigene expression caused by PcG deficiency. The suppression of ectopic Ubx expression correlated with reduced chromatin accessibility of the Ubx promoter. To our knowledge, this is the first in vivo evidence for deficiency of a SMARCAL1 ortholog altering the chromatin structure of a gene.
机译：SMARCAL1中的突变编码一种DNA退火解旋酶，在DNA复制叉重启，DNA修复和基因表达调控中起作用，引起Schimke免疫性骨发育不良（SIOD），这是一种常染色体隐性遗传疾病，特征在于骨骼发育不良，肾脏疾病，T-细胞免疫缺陷和动脉硬化。 SIOD的临床特征来自基因表达的病理变化。然而，这些基因表达改变的潜在机制仍不清楚。我们假设表观基因组的变化会改变SIOD中的基因表达。为了测试这一点，我们对Marcal1，果蝇SMARCAL1的果蝇直向同源物以及编码表观遗传调控因子的胸廓（trxG）和Polycomb组（PcG）的基因之间的相互作用进行了遗传筛选。 SMARCAL1和Marcal1与trxG和PcG成员发生了基因相互作用。 Marcal1的纯合无效突变抑制了由PcG缺乏引起的机翼到三角架的转化，异位Ultrabithorax（Ubx）表达和异位Ubx minigene表达。异位Ubx表达的抑制与Ubx启动子的染色质可及性降低有关。据我们所知，这是SMARCAL1直向同源物改变基因染色质结构缺陷的第一个体内证据。

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