MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression
MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression
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DOI：
10.1093/hmg/ddx099
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发表时间：
2017-06-01
影响因子：
3.5
通讯作者：
Egly, Jean-Marc
中科院分区：
文献类型：
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作者：
Donnio, Lise-Marie;Bidon, Baptiste;Egly, Jean-Marc
在蛋白质编码基因表达中，Mediator在介导基因特异性因子与基础转录机制之间的联系中起着关键作用，但对每个Mediator亚基的作用知之甚少。MED12突变与广泛的遗传疾病与x连锁智力残疾有关，这些疾病难以归类为Lujan、Opitz-Kaveggia或Ohdo综合征。在这里，我们研究了几种MED12患者的突变（p. R206Q, p. N898D, p. R961W, p. N1007S, p. R1148H, p. S1165P和p. R1295H），发现每种MED12突变都会导致JUN、FOS和EGR1即时早期基因（eggs）的特异性表达模式，这可以通过在各自的启动子上是否存在MED12含复合物来反映。此外，MED12突变对IEG表达的影响具有细胞类型特异性。因此，晚期反应基因如基质金属蛋白酶-3和RE1沉默转录因子的表达分别涉及神经可塑性和神经元基因的特异性表达受到干扰，如MED12/p所述。R1295H突变。在这种情况下，JUN和FOS未能在其ap1结合位点得到适当的招募。我们的研究结果表明，med12相关表型之间的差异本质上是不同的eeg表达模式的结果，后者取决于转录起始复合物的准确形成。这可能会挑战临床医生重新思考传统的综合征界限，并将遗传标准纳入患者的诊断。
Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p. R206Q, p. N898D, p. R961W, p. N1007S, p. R1148H, p. S1165P and p. R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p. R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.