DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells.
DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells.
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DNMT3A单倍不足导致成熟人类免疫细胞中增强子处的二分DNA甲基化缺陷。
DOI：
10.1084/jem.20202733
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Byun M
中科院分区：
文献类型：
--
作者：
Lim JY;Duttke SH;Baker TS;Lee J;Gambino KJ;Venturini NJ;Ho JSY;Zheng S;Fstkchyan YS;Pillai V;Fajgenbaum DC;Marazzi I;Benner C;Byun M
DNMT3A的获得性突变在血液中很常见，但它们对成熟免疫细胞的影响却知之甚少。Lim等人证明，DNMT3A缺陷导致增强子处的二分DNA甲基化缺陷，导致成熟免疫细胞中增强子活性改变和基因表达异常。DNMT3A编码一种进行从头DNA甲基化的酶，这对于在细胞分化期间获得细胞身份和专门功能至关重要。DNMT3A是年龄相关性克隆性造血中最常发生突变的基因。因此，携带DNMT3A突变的成熟免疫细胞可以在老年人中容易地检测到。大多数与克隆性造血相关的DNMT3A突变是杂合的，并预测会导致功能丧失，表明单倍不足是主要的致病机制。然而，DNMT3A单倍不足对成熟免疫细胞功能的影响知之甚少。在这里，我们证明了DNMT3A单倍不足损害了在退役增强子处的DNA甲基化的获得，同时意外地损害了成熟人骨髓细胞中新激活的增强子的DNA去甲基化。DNA甲基化缺陷改变了受影响的增强子的活性，导致基因表达异常和免疫反应受损。这些发现提供了与克隆造血和获得性DNMT3A突变相关的免疫功能障碍机制的见解。
Acquired mutations in DNMT3A are common in blood, but their impacts on mature immune cells are poorly understood. Lim et al. demonstrate that DNMT3A defects cause dichotomous DNA methylation defects at enhancers, leading to altered enhancer activity and abnormal gene expression in mature immune cells. DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly persons. Most DNMT3A mutations associated with clonal hematopoiesis are heterozygous and predicted to cause loss of function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, the impact of DNMT3A haploinsufficiency on the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairing DNA demethylation of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with clonal hematopoiesis and acquired DNMT3A mutations.
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影响因子：
7
作者：
Duttke, Sascha H.;Chang, Max W.;Benner, Christopher
通讯作者：
Benner, Christopher
影响因子：
14.9
作者：
Feng H;Conneely KN;Wu H
通讯作者：
Wu H
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
11.4
作者：
Dawoud, Ahmed A. Z.;Tapper, William J.;Cross, Nicholas C. P.
通讯作者：
Cross, Nicholas C. P.
影响因子：
11.4
作者：
Arends, Christopher Maximilian;Galan-Sousa, Joel;Damm, Frederik
通讯作者：
Damm, Frederik