Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.
Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.
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DOI：
10.1007/s00018-021-03822-w
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Forsberg LA
中科院分区：
文献类型：
--
作者：
Dumanski JP;Halvardson J;Davies H;Rychlicka-Buniowska E;Mattisson J;Moghadam BT;Nagy N;Węglarczyk K;Bukowska-Strakova K;Danielsson M;Olszewski P;Piotrowski A;Oerton E;Ambicka A;Przewoźnik M;Bełch Ł;Grodzicki T;Chłosta PL;Imreh S;Giedraitis V;Kilander L;Nordlund J;Ameur A;Gyllensten U;Johansson Å;Józkowicz A;Siedlar M;Klich-Rączka A;Jaszczyński J;Enroth S;Baran J;Ingelsson M;Perry JRB;Ryś J;Forsberg LA
流行病学调查表明，白细胞中Y染色体嵌合丢失（LOY）与男性许多疾病的早期死亡和发病有关。LOY是最常见的获得性突变，与细胞的异常克隆扩增有关，但目前尚不清楚这种嵌合现象是否产生直接的生理效应。我们研究了DNA和RNA从白细胞在分选和单细胞在体内和体外。分选细胞的DNA分析显示，被诊断患有阿尔茨海默病的男性主要受到NK细胞中LOY的影响，而前列腺癌患者更频繁地在CD 4 + T细胞和粒细胞中显示LOY。此外，在白细胞中的批量和单细胞RNA测序允许从mRNA数据中对LOY进行评分，并证实了个体和细胞类型之间LOY率的相当大的变化。LOY相关转录效应（LATE）在约500个常染色体基因中观察到，显示LOY白细胞中的失调。LATE基因在特定细胞类型中的比例远大于不同白细胞亚群之间共享的LATE基因的比例，表明LOY可能具有多效性效应。LATE基因参与免疫功能，但也编码在其他不同生物过程中发挥作用的蛋白质。我们的研究结果突出了Y染色体的惊人广泛作用，挑战了它作为“遗传荒地”的观点，并支持白细胞免疫功能改变可能是LOY与疾病风险增加相关的机制的假设。在线版本包含补充材料，可通过10.1007/s 00018 -021-03822-w获得。
Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease. The online version contains supplementary material available at 10.1007/s00018-021-03822-w.
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影响因子：
11.2
作者：
AlHossiny M;Luo L;Frazier WR;Steiner N;Gusev Y;Kallakury B;Glasgow E;Creswell K;Madhavan S;Kumar R;Upadhyay G
通讯作者：
Upadhyay G
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通讯作者：
Forsberg LA
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64.8
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影响因子：
5.3
作者：
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通讯作者：
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