The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.
The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.
复制标题
mRNA m6A阅读器YTHDF2抑制促炎通路并维持造血干细胞功能。
DOI：
10.1084/jem.20200829
复制
发表时间：
2021-03-01
期刊：
影响因子：
--
通讯作者：
Kranc KR
中科院分区：
文献类型：
--
作者：
Mapperley C;van de Lagemaat LN;Lawson H;Tavosanis A;Paris J;Campos J;Wotherspoon D;Durko J;Sarapuu A;Choe J;Ivanova I;Krause DS;von Kriegsheim A;Much C;Morgan M;Gregory RI;Mead AJ;O'Carroll D;Kranc KR
m6 A阅读器YTHDF 2是HSC中炎症通路的新型调节剂。YTHDF 2缺失上调m6 A修饰的促炎转录物，导致慢性HSC炎性激活、髓样偏向和功能衰竭。mRNA N6-甲基腺苷（m6 A）修饰已成为正常和恶性造血的重要调节因子。识别m6 A修饰的转录物以促进m6 A-mRNA降解的m6 A mRNA阅读器YTHDF 2的失活导致造血干细胞（HSC）扩增并损害急性髓性白血病。在这里，我们研究了YTHDF 2缺失对HSC维持和多系造血的长期影响。我们证明了来自年轻小鼠的Ythdf 2缺陷型HSC在连续移植后失败，显示出多个m6 A修饰的炎症相关转录物的丰度增加，并长期激活促炎通路。与HSC中炎性通路慢性活化的有害后果一致，造血特异性Ythdf 2缺陷导致进行性骨髓偏向、淋巴潜能丧失、HSC扩增和老化的Ythdf 2缺陷型HSC重建多系造血的失败。实验诱导的炎症增加了YTHDF 2的表达，并且需要YTHDF 2来保护HSC免受这种损伤。因此，我们的研究将YTHDF 2定位为HSC中炎症通路的阻遏物，并强调了m6 A在长期HSC维持中的重要性。
The m6A reader YTHDF2 is a novel regulator of inflammatory pathways in HSCs. YTHDF2 loss upregulates m6A-modified proinflammatory transcripts, resulting in chronic HSC inflammatory activation, myeloid bias, and functional exhaustion. The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.
登录
查看更多内容
DOI：
10.1084/jem.20161087
发表时间：
2017-03-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guitart AV;Panagopoulou TI;Villacreces A;Vukovic M;Sepulveda C;Allen L;Carter RN;van de Lagemaat LN;Morgan M;Giles P;Sas Z;Gonzalez MV;Lawson H;Paris J;Edwards-Hicks J;Schaak K;Subramani C;Gezer D;Armesilla-Diaz A;Wills J;Easterbrook A;Coman D;So CW;O'Carroll D;Vernimmen D;Rodrigues NP;Pollard PJ;Morton NM;Finch A;Kranc KR
通讯作者：
Kranc KR
DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
YTHDF2 通过直接招募 CCR4-NOT 去腺苷酶复合物来破坏含有 m(6)A 的 RNA 的稳定性。
影响因子：
16.6
作者：
Du, Hao;Zhao, Ya;He, Jinqiu;Zhang, Yao;Xi, Hairui;Liu, Mofang;Ma, Jinbiao;Wu, Ligang
通讯作者：
Wu, Ligang
影响因子：
50.3
作者：
Li Z;Weng H;Su R;Weng X;Zuo Z;Li C;Huang H;Nachtergaele S;Dong L;Hu C;Qin X;Tang L;Wang Y;Hong GM;Huang H;Wang X;Chen P;Gurbuxani S;Arnovitz S;Li Y;Li S;Strong J;Neilly MB;Larson RA;Jiang X;Zhang P;Jin J;He C;Chen J
通讯作者：
Chen J
影响因子：
14.9
作者：
Ramírez F;Dündar F;Diehl S;Grüning BA;Manke T
通讯作者：
Manke T