TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells
Lise Secardin1, Cintia Elisabeth Gomez Limia2, Antonio di Stefano1
1INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France; Université Paris XI, UMR 1170, Gustave Roussy, Villejuif, France; UMR U1170,Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France; Laboratory of Excellence GR-Ex, Villejuif, France.
Stem Cell Research
|March 21, 2020
Summary
Endogenous TET2 protein is crucial for reprogramming human hematopoietic progenitor cells into induced pluripotent stem cells (iPSC). TET2 mutations in myeloproliferative neoplasms (MPN) can restore iPSC generation, suggesting altered TET protein function in disease.
Area of Science:
- Epigenetics and Cellular Reprogramming
- Hematopoiesis and Cancer Biology
- DNA Methylation Dynamics
Background:
- The Ten-Eleven Translocation (TET) protein family (TET1, TET2, TET3) modifies DNA methylation, converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and further oxidized forms.
- TET proteins are implicated in cellular reprogramming into induced pluripotent stem cells (iPSC), with TET1 and TET2 shown to be important in mouse models and TET1 in human cells.
- Mutations in TET2 are frequently observed in hematological malignancies, including myeloproliferative neoplasms (MPN), hinting at its role in both normal development and disease.
Purpose of the Study:
- To investigate the role of endogenous TET2 in the reprogramming of human hematopoietic progenitor cells (HPCs) into iPSCs.
- To determine if TET2 mutations found in MPN affect the reprogramming potential of HPCs.
- To explore the impact of combined TET2 and TET3 mutations on iPSC generation.
Main Methods:
- Knockdown of endogenous TET2 in human HPCs using short hairpin RNA (shRNA).
- Assessment of iPSC reprogramming efficiency following TET2 knockdown.
- Analysis of iPSC generation from HPCs of MPN patients with specific TET2 and/or TET3 mutations.
Main Results:
- Endogenous TET2 knockdown significantly impaired the reprogramming of human HPCs into iPSCs.
- HPCs from MPN patients with TET2 mutations in the catalytic domain showed restored iPSC generation capacity.
- iPSC generation was successful in a patient with a TET3 mutation alone, but not with combined TET2 and TET3 mutations, suggesting differential effects based on mutation type and cooperation.
Conclusions:
- Endogenous TET2 plays a critical role in suppressing the reprogramming of human hematopoietic progenitor cells.
- TET2 mutations in MPN can alter its function, potentially enabling iPSC generation.
- The specific type of TET mutation and its interaction with other TET family members influence reprogramming efficiency, highlighting the complex role of TET proteins in cellular plasticity.
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