Screening for genes that regulate the differentiation of human megakaryocytic lineage cells

Fangfang Zhu, Mingye Feng, Rahul Sinha, Jun Seita, Yasuo Mori, Irving L. Weissman

研究成果: Contribution to journalArticle査読

11 被引用数 (Scopus)

抄録

Different combinations of transcription factors (TFs) function at each stage of hematopoiesis, leading to distinct expression patterns of lineage-specific genes. The identification of such regulators and their functions in hematopoiesis remain largely unresolved. In this study, we utilized screening approaches to study the transcriptional regulators of megakaryocyte progenitor (MkP) generation, a key step before platelet production. Promising candidate genes were generated from a microarray platform gene expression commons and individually manipulated in human hematopoietic stem and progenitor cells (HSPCs). Deletion of some of the candidate genes (the hit genes) by CRISPR/Cas9 led to decreased MkP generation during HSPC differentiation, while more MkPs were produced when some hit genes were overexpressed in HSPCs.We then demonstrated that overexpression of these genes can increase the frequency of mature megakaryocytic colonies by functional colony forming unitmegakaryocyte (CFU-Mk) assay and the release of platelets after in vitro maturation. Finally, we showed that the histone deacetylase inhibitors could also increase MkP differentiation, possibly by regulating some of the newly identified TFs. Therefore, identification of such regulators will advance the understanding of basic mechanisms of HSPC differentiation and conceivably enable the generation and maturation of megakaryocytes and platelets in vitro.

本文言語英語
ページ(範囲)E9308-E9316
ジャーナルProceedings of the National Academy of Sciences of the United States of America
115
40
DOI
出版ステータス出版済み - 10 2 2018
外部発表はい

All Science Journal Classification (ASJC) codes

  • 一般

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