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Screening for genes that regulate the differentiation of human megakaryocytic lineage cells
- Publication Year :
- 2018
- Publisher :
- National Academy of Sciences, 2018.
-
Abstract
- 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 unit-megakaryocyte (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.
- Subjects :
- 0301 basic medicine
Candidate gene
Conservation of Natural Resources
Multidisciplinary
Hematopoietic System
Biology
Cell biology
03 medical and health sciences
Haematopoiesis
030104 developmental biology
PNAS Plus
Gene expression
Gene Regulatory Networks
Histone deacetylase
Progenitor cell
Gene
Transcription factor
Progenitor
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....9f822f44323d1486450916718e868d21