KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia.
KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia.
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DOI：
10.1182/bloodadvances.2020002842
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发表时间：
2022-01-11
期刊：
影响因子：
7.5
通讯作者：
Pina C
中科院分区：
文献类型：
--
作者：
Arede L;Foerner E;Wind S;Kulkarni R;Domingues AF;Giotopoulos G;Kleinwaechter S;Mollenhauer-Starkl M;Davison H;Chandru A;Asby R;Samarista R;Gupta S;Forte D;Curti A;Scheer E;Huntly BJP;Tora L;Pina C
KAT2A 在人类脐带血红细胞发育的不同阶段都是必需的，具有 ATAC 和 SAGA 复合体特异性。 KAT2A 通过特定参与 ATAC 和 SAGA 复合物来调节白血病细胞的维持和身份。表观遗传组蛋白修饰剂是正常和恶性造血过程中细胞命运决定的关键调节因子。它们的酶活性作为白血病的假定治疗靶点具有特别重要的意义。相比之下，人们对这些酶活性发挥的背景作用以及具体不同的大分子复合物如何配置具有不同分子和细胞后果的相同酶活性知之甚少。我们重点关注 KAT2A，一种负责组蛋白 H3 赖氨酸 9 乙酰化的赖氨酸乙酰转移酶，我们最近发现它是急性髓性白血病干细胞的依赖性，并且参与 2 个不同的大分子复合物：Ada 含二 A (ATAC) 和 Spt-Ada-Gcn5-乙酰转移酶 (SAGA)。通过对人脐带血造血干细胞和祖细胞以及骨髓性白血病细胞的分析，我们确定了 ATAC 复合物对调节未分化自我更新细胞的生物合成活性以及 SAGA 复合物对稳定或纠正细胞类型特异性程序的进展以及假定的细胞身份的保存的独特贡献。细胞类型和阶段特定对 ATAC 和 SAGA 监管程序的依赖性解释了白血病和红细胞谱系规范和发育中的多级 KAT2A 需求。重要的是，他们建立了一个范例，可以根据该范例在发育干细胞系统中探索谱系规范和身份。
KAT2A is required at different stages of human cord blood erythroid development with ATAC and SAGA complex specificity. KAT2A regulates leukemia cell maintenance and identity through specific participation in ATAC and SAGA complexes. Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised and specifically how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for histone H3 lysine 9 acetylation, which we recently identified as a dependence in acute myeloid leukemia stem cells and that participates in 2 distinct macromolecular complexes: Ada two-A-containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells and of the SAGA complex to stabilization or correct progression of cell type–specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multilevel KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
3.7
作者：
Martínez-Cerdeño V;Lemen JM;Chan V;Wey A;Lin W;Dent SR;Knoepfler PS
通讯作者：
Knoepfler PS
影响因子：
7.7
作者：
Carre, Clement;Ciurciu, Anita;Antoniewski, Christophe
通讯作者：
Antoniewski, Christophe
影响因子：
4.8
作者：
Lam, LT;Ronchini, C;Bresnick, EH
通讯作者：
Bresnick, EH
影响因子：
64.5
作者：
Khajuria RK;Munschauer M;Ulirsch JC;Fiorini C;Ludwig LS;McFarland SK;Abdulhay NJ;Specht H;Keshishian H;Mani DR;Jovanovic M;Ellis SR;Fulco CP;Engreitz JM;Schütz S;Lian J;Gripp KW;Weinberg OK;Pinkus GS;Gehrke L;Regev A;Lander ES;Gazda HT;Lee WY;Panse VG;Carr SA;Sankaran VG
通讯作者：
Sankaran VG