Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia.
Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia.
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DOI：
10.1101/gr.171645.113
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发表时间：
2014-12
期刊：
影响因子：
7
通讯作者：
Holländer GA
中科院分区：
文献类型：
--
作者：
Sansom SN;Shikama-Dorn N;Zhanybekova S;Nusspaumer G;Macaulay IC;Deadman ME;Heger A;Ponting CP;Holländer GA
胸腺上皮细胞（TEC）的混杂基因表达（PGE）对于产生耐受自身抗原的多样性T细胞抗原受体库，从而避免自身免疫是必不可少的。然而，TEC群体和单细胞内这种不寻常的表达程序的程度和性质是未知的。通过对仔细鉴定的小鼠TEC亚群进行深度转录组测序，我们发现了一个在髓质（m）和皮质TEC之间常见的PGE程序，该程序在mTEC中进一步阐述，并在表达自身免疫调节基因（Aire）的成熟mTEC中完成。TEC群体能够表达多达19，293个蛋白质编码基因，这是已知在任何细胞类型中表达的最高数量的基因。值得注意的是，在小鼠mTEC中，Aire表达单独正向调节3980个组织限制性基因。值得注意的是，这些基因的组织特异性包括人类AIRE缺乏症中自身免疫的已知靶标。通过观察到由Aire表达诱导的基因通常以体细胞组织中的抑制性染色质状态为特征，我们发现这些基因与mTEC中的H3K27me3标记密切相关。我们的研究结果与AIRE靶向和诱导先前被Polycomb组蛋白质表观遗传沉默的基因的混杂表达一致。比较174个单个mTEC的转录组表明，Aire表达诱导的基因在低细胞频率下随机转录。此外，当存在时，Aire表达依赖性转录水平平均在个体TEC中比在mTEC群体中高16倍。
Promiscuous gene expression (PGE) by thymic epithelial cells (TEC) is essential for generating a diverse T cell antigen receptor repertoire tolerant to self-antigens, and thus for avoiding autoimmunity. Nevertheless, the extent and nature of this unusual expression program within TEC populations and single cells are unknown. Using deep transcriptome sequencing of carefully identified mouse TEC subpopulations, we discovered a program of PGE that is common between medullary (m) and cortical TEC, further elaborated in mTEC, and completed in mature mTEC expressing the autoimmune regulator gene (Aire). TEC populations are capable of expressing up to 19,293 protein-coding genes, the highest number of genes known to be expressed in any cell type. Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-restricted genes. Notably, the tissue specificities of these genes include known targets of autoimmunity in human AIRE deficiency. Led by the observation that genes induced by Aire expression are generally characterized by a repressive chromatin state in somatic tissues, we found these genes to be strongly associated with H3K27me3 marks in mTEC. Our findings are consistent with AIRE targeting and inducing the promiscuous expression of genes previously epigenetically silenced by Polycomb group proteins. Comparison of the transcriptomes of 174 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low cell frequency. Furthermore, when present, Aire expression-dependent transcript levels were 16-fold higher, on average, in individual TEC than in the mTEC population.
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DOI：
10.1126/science.1159407
发表时间：
2008-08-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gardner JM;Devoss JJ;Friedman RS;Wong DJ;Tan YX;Zhou X;Johannes KP;Su MA;Chang HY;Krummel MF;Anderson MS
通讯作者：
Anderson MS
影响因子：
3.7
作者：
de Jonge HJ;Fehrmann RS;de Bont ES;Hofstra RM;Gerbens F;Kamps WA;de Vries EG;van der Zee AG;te Meerman GJ;ter Elst A
通讯作者：
ter Elst A
影响因子：
14.9
作者：
Gaetani M;Matafora V;Saare M;Spiliotopoulos D;Mollica L;Quilici G;Chignola F;Mannella V;Zucchelli C;Peterson P;Bachi A;Musco G
通讯作者：
Musco G
影响因子：
32.4
作者：
Ernst, B;Lee, DS;Surh, CD
通讯作者：
Surh, CD
影响因子：
14.9
作者：
Flicek P;Ahmed I;Amode MR;Barrell D;Beal K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fairley S;Fitzgerald S;Gil L;García-Girón C;Gordon L;Hourlier T;Hunt S;Juettemann T;Kähäri AK;Keenan S;Komorowska M;Kulesha E;Longden I;Maurel T;McLaren WM;Muffato M;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ritchie GR;Ruffier M;Schuster M;Sheppard D;Sobral D;Taylor K;Thormann A;Trevanion S;White S;Wilder SP;Aken BL;Birney E;Cunningham F;Dunham I;Harrow J;Herrero J;Hubbard TJ;Johnson N;Kinsella R;Parker A;Spudich G;Yates A;Zadissa A;Searle SM
通讯作者：
Searle SM