Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Department of Paediatrics, University of Oxford, Oxford United Kingdom.
Front Immunol. 2018 Sep 19;9:2120. doi: 10.3389/fimmu.2018.02120. eCollection 2018.
Thymic epithelial cells (TEC) effect crucial roles in thymopoiesis including the control of negative thymocyte selection. This process depends on their capacity to express promiscuously genes encoding tissue-restricted antigens. This competence is accomplished in medullary TEC (mTEC) in part by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. When during TEC development these chromatin marks are established, however, remains unclear. Here we use a comprehensive ChIP-seq dataset of multiple chromatin modifications in different TEC subtypes to demonstrate that the chromatin landscape is established early in TEC differentiation. Much of the chromatin architecture found in mature mTEC was found to be present already over earlier stages of mTEC lineage differentiation as well as in non-TEC tissues. This was reflected by the fact that a machine learning approach accurately classified genes as AIRE-induced or AIRE-independent both in immature and mature mTEC. Moreover, analysis of TEC specific enhancer elements identified candidate transcription factors likely to be important in mTEC development and function. Our findings indicate that the mature mTEC chromatin landscape is laid down early in mTEC differentiation, and that AIRE is not required for large-scale re-patterning of chromatin in mTEC.
胸腺上皮细胞（TEC）在胸腺生成中发挥着至关重要的作用，包括控制负性胸腺细胞的选择。这一过程依赖于它们表达随意基因的能力，这些基因编码组织受限的抗原。这种能力在髓质 TEC（mTEC）中部分是通过转录辅助因子自身免疫调节剂（AIRE）的存在来实现的。AIRE 调节的基因转录被抑制性染色质修饰标记，包括 H3K27me3。然而，在 TEC 发育过程中，这些染色质标记是如何建立的仍不清楚。在这里，我们使用了多个 TEC 亚型中多种染色质修饰的综合 ChIP-seq 数据集，证明了染色质景观在 TEC 分化的早期就已经建立。在成熟的 mTEC 中发现的大部分染色质结构已经存在于 mTEC 谱系分化的早期阶段以及非 TEC 组织中。这一事实反映在机器学习方法能够准确地将基因分类为 AIRE 诱导或 AIRE 不依赖的基因，无论是在不成熟的还是成熟的 mTEC 中。此外，对 TEC 特异性增强子元件的分析确定了候选转录因子，这些因子可能在 mTEC 发育和功能中很重要。我们的研究结果表明，成熟的 mTEC 染色质景观在 mTEC 分化的早期就已经建立，而 AIRE 并不需要 mTEC 中染色质的大规模重新模式化。
