Mouse models of neutropenia reveal progenitor-stage-specific defects.
Mouse models of neutropenia reveal progenitor-stage-specific defects.
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DOI：
10.1038/s41586-020-2227-7
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发表时间：
2020-06
期刊：
影响因子：
64.8
通讯作者：
Grimes HL
中科院分区：
文献类型：
--
作者：
Muench DE;Olsson A;Ferchen K;Pham G;Serafin RA;Chutipongtanate S;Dwivedi P;Song B;Hay S;Chetal K;Trump-Durbin LR;Mookerjee-Basu J;Zhang K;Yu JC;Lutzko C;Myers KC;Nazor KL;Greis KD;Kappes DJ;Way SS;Salomonis N;Grimes HL
遗传学和测序的进展揭示了大量与疾病相关和致病的遗传改变。解决遗传学和疾病之间的因果关系需要生成精确的分子解剖模型;然而，单细胞景观的快速扩展对突变体及其野生型等同物之间的准确比较提出了重大挑战。在这里，我们产生了人类严重先天性中性粒细胞减少症（SCN）的小鼠模型，使用患者来源的突变的生长因子非依赖性-1（GFI 1）转录因子。为了描述SCN突变的影响，我们生成了具有连接表位的粒细胞生成基因组状态的单细胞参考，将突变细胞与其野生型等同物对齐，并鉴定了差异表达的基因和表观遗传基因座。我们发现，Gfi 1靶基因顺序改变，细胞在分化过程中遍历连续的状态。这些细胞状态特异性的见解促进了粒细胞特异性的遗传拯救，但不是先天免疫效应子功能中的定型后缺陷;强调了评估每个相关细胞状态中突变和治疗的影响的重要性。
Advances in genetics and sequencing reveal a plethora of disease-associated and disease-causing genetic alterations. Resolving causality between genetics and disease requires generating accurate models for molecular dissection; however, the rapid expansion of single-cell landscapes presents a major challenge to accurate comparisons between mutants and their wild-type equivalents. Here, we generated mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the Growth factor independent-1 (GFI1) transcription factor. To delineate the impact of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalent and identified differentially expressed genes and epigenetic loci. We find that Gfi1-target genes are altered sequentially, as cells traverse successive states during differentiation. These cell-state-specific insights facilitated genetic rescue of granulocytic specification but not post-commitment defects in innate-immune effector function; underscoring the importance of evaluating the impact of mutations and therapy within each relevant cell state.
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影响因子：
48
作者：
Stoeckius M;Hafemeister C;Stephenson W;Houck-Loomis B;Chattopadhyay PK;Swerdlow H;Satija R;Smibert P
通讯作者：
Smibert P
DOI：
10.4049/jimmunol.1001893
发表时间：
2011-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
MacNamara KC;Oduro K;Martin O;Jones DD;McLaughlin M;Choi K;Borjesson DL;Winslow GM
通讯作者：
Winslow GM
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
64.8
作者：
Olsson, Andre;Venkatasubramanian, Meenakshi;Chaudhri, Viren K.;Aronow, Bruce J.;Salomonis, Nathan;Singh, Harinder;Grimes, H. Leighton
通讯作者：
Grimes, H. Leighton
影响因子：
8.8
作者：
Bonthuis, Paul J.;Huang, Wei-Chao;Gregg, Christopher
通讯作者：
Gregg, Christopher