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Published on: November 18, 2009
A shRNA functional screen reveals Nme6 and Nme7 are crucial for embryonic stem cell renewal
Chia-Hui Wang1, Nianhan Ma, Yu-Tsen Lin
1Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Abstract:
In contrast to the somatic cells, embryonic stem cells (ESCs) are characterized by its immortalization ability, pluripotency, and oncogenicity. Revealing the underlying mechanism of ESC characteristics is important for the application of ESCs in clinical medicine. We performed systematic functional screen in mouse ESCs with 4,801 shRNAs that target 929 kinases and phosphatases. One hundred and thirty-two candidate genes that regulate both ESC expansion and stem cell marker expression were identified. Twenty-seven out of the 132 genes were regarded as most important since knockdown of each gene induces morphological changes from undifferentiated to differentiated state. Among the 27 genes, we chose nonmetastatic cell 6 (Nme6, also named as Nm23-H6) and nonmetastatic cell 7 (Nme7, also designated as Nm23-H7) to study first. Nme6 and Nme7 both belong to the members of nucleoside diphosphate kinase family. We demonstrate that Nme6 and Nme7 are important for the regulation of Oct4, Nanog, Klf4, c-Myc, telomerase, Dnmt3B, Sox2, and ERas expression. Either knockdown of Nme6 or Nme7 reduces the formation of embryoid body (EB) and teratoma. The overexpression of either Nme6 or Nme7 can rescue the stem cell marker expression and the EB formation in the absence of leukemia inhibiting factor. This implies the importance of Nme6 and Nme7 in ESC renewal. This finding not only pinpoints Nme6 or Nme7 can regulate several critical regulators in ESC renewal but also increases our understanding of the ESC renewal and oncogenesis.
Insights
Two nucleoside diphosphate kinase family members, Nme6 and Nme7, are crucial for maintaining embryonic stem cell (ESC) renewal and pluripotency. Their regulation impacts key stem cell markers and oncogenic potential.
Area of Science:
- Stem Cell Biology
- Molecular Oncology
- Gene Regulation
Background:
- Embryonic stem cells (ESCs) possess unique properties like self-renewal and pluripotency, essential for development and regenerative medicine.
- Understanding the molecular mechanisms governing ESC characteristics, including immortalization and oncogenicity, is critical for clinical applications.
Purpose of the Study:
- To identify novel regulators of embryonic stem cell (ESC) expansion and pluripotency through a large-scale functional screen.
- To investigate the specific roles of identified genes, particularly Nme6 and Nme7, in maintaining ESC identity and self-renewal.
Main Methods:
- A systematic functional screen using 4,801 shRNAs targeting 929 kinases and phosphatases in mouse ESCs.
- Identification of candidate genes regulating ESC expansion and stem cell marker expression.
- Knockdown and overexpression studies of Nme6 and Nme7 to assess their impact on stem cell markers, differentiation, and self-renewal capacity.
Main Results:
- Identified 132 candidate genes regulating ESC expansion and stem cell markers; 27 were critical for maintaining the undifferentiated state.
- Nme6 and Nme7 were identified as key regulators, influencing Oct4, Nanog, Klf4, c-Myc, telomerase, Dnmt3B, Sox2, and ERas expression.
- Knockdown of Nme6 or Nme7 impaired embryoid body (EB) and teratoma formation, while their overexpression rescued stem cell marker expression and EB formation.
Conclusions:
- Nme6 and Nme7 are essential for embryonic stem cell (ESC) renewal, regulating critical factors involved in pluripotency and self-renewal.
- These findings enhance the understanding of ESC renewal mechanisms and their connection to oncogenesis.
- Nme6 and Nme7 represent potential therapeutic targets for controlling stem cell behavior in regenerative medicine and cancer therapy.
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