Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs.
Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs.
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DOI：
10.1182/bloodadvances.2021006325
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发表时间：
2022-05-24
期刊：
影响因子：
7.5
通讯作者：
Papapetrou, Eirini P.
中科院分区：
文献类型：
--
作者：
Asimomitis, Georgios;G. Deslaurnes, Andre;Kotini, Andriana G.;Bernard, Elsa;Esposito, Davide;Olszewska, Malgorzata;Spyrou, Nikolaos;Ossa, Juan Arango;Mortera-Blanco, Teresa;Koche, Richard;Malcovati, Luca;Ogawa, Seishi;Cazzola, Mario;Aaronson, Stuart A.;Hellstro-Lindberg, Eva;Papaemmanuil, Elli;Nannya, Yasuhito;Papapetrou, Eirini P.
利用基因匹配的MDS-RS和正常患者特异性iPSC-HSPCs获得突变的SF3B1剪接特征。整合转录组学和染色质可及性表明，TEAD可能是SF3B1K700E细胞的一种新的转录调节因子。SF3B1K700E是骨髓增生异常综合征（MDS）中最常见的突变，但其驱动MDS发病的机制尚不清楚。我们从MDS患者身上获得了18个基因匹配的SF3B1K700E-和sf3b1wt诱导的多能干细胞（iPSC）细胞系，这些细胞系含有分离的SF3B1K700E突变，并对来自它们的纯化的CD34+/CD45+造血干细胞/祖细胞（HSPCs）进行了RNA和ATAC测序。我们开发了一个新的计算框架，将剪接与转录物使用和基因表达分析结合起来，并获得了一个由59个剪接事件组成的SF3B1K700E剪接特征，这些剪接事件与34个基因有关，这与原发性MDS患者细胞的SF3B1突变状态有关。SF3B1K700E HSPCs的染色质景观显示向巨核细胞-红细胞谱系的启动增加。意想不到的是，SF3B1K700E细胞中染色质区域富集的转录因子基元包括TEA结构域（TEAD）转录因子家族的基元。在sf3b1突变ipsc - hspc中，TEAD的表达和转录活性上调，支持TEAD作为SF3B1K700E细胞的潜在新型转录调节因子的Hippo通路独立作用。本研究提供了SF3B1K700E HSPCs转录和染色质景观的全面表征，并提名了新的错误剪接基因和转录程序，这些基因和转录程序可能在MDS-RS疾病生物学中起作用。
Genetically matched MDS-RS and normal patient-specific iPSC-HSPCs are used to derive a mutant SF3B1 splicing signature. Integrated transcriptomics and chromatin accessibility nominate TEAD as a putative novel transcriptional regulator of SF3B1K700E cells. SF3B1K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1K700E- and SF3B1WT-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1K700E mutations and performed RNA and ATAC sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1K700E HSPCs showed increased priming toward the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1K700E cells included, unexpectedly, motifs of the TEA domain (TEAD) transcription factor family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.
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影响因子：
11.4
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影响因子：
82.9
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
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Papaemmanuil E
影响因子：
48
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通讯作者：
Salzberg, Steven L.
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6.2
作者：
Kanagal-Shamanna, Rashmi;Montalban-Bravo, Guillermo;Garcia-Manero, Guillermo
通讯作者：
Garcia-Manero, Guillermo
影响因子：
23.9
作者：
Kotini, Andriana G.;Chang, Chan-Jung;Papapetrou, Eirini P.
通讯作者：
Papapetrou, Eirini P.