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P-Bodies Linked to Cell-Fate Transitions in Stem Cells

Key findings

  • This study concerns DDX6, an enzyme in RNA that's essential to assembly of processing-bodies (P-bodies), key sites of post-transcriptional control
  • Pluripotent stem cells that lacked DDX6 lost P-bodies and could not exit pluripotency or differentiate, whereas suppression of DDX6 promoted the reprogramming of both mouse and human embryonic stem cells to a naive state
  • DDX6 regulated the differentiation potential of adult progenitors in a context-dependent manner
  • DDX6 loss resulted in disassembly of P-bodies, which released mRNAs to translational machinery; increased protein levels of transcription and chromatin factors then potently influenced the fate of embryonic and adult stem cells
  • Findings related to the stability of stem cell fate and identity are relevant to cancer research, in part to discover how to "reprogram" stem cells to change their fate in more targeted, therapeutically relevant ways

Processing bodies (P-bodies) are key sites of post-transcriptional control in cells. These cytoplasmic organelles form after RNAs and RNA binding proteins assemble into ribonucleoprotein particle granules. P-bodies primarily control the storage of untranslated mRNAs by sequestering them from the translational machinery.

Independent of transcription, the mRNAs in P-bodies can be rapidly reintroduced into the translating poolfor example, in response to certain environmental cues. However, whether and how P-bodies function in developmental transitions has been unclear.

Konrad Hochedlinger, PhD, investigator in the Center for Cancer Research, Massachusetts General Hospital Cancer Center, and colleagues have uncovered a previously unrecognized role for P-bodies in stabilizing cell identity. In Cell Stem Cell, they explain that P-bodies modulate the storage of mRNAs encoding for key cell fate–instructive proteins.

DDX6 Safeguards Cell Identity

The researchers conducted in vitro research on DDX6, an enzyme in RNA that's essential for P-body assembly. They found DDX6 to be a crucial regulator of mouse and human cell-fate control:

  • DDX6-mediated gene regulation was required for a stem cell to exit the pluripotent state and properly differentiate
  • Conversely, DDX6 suppression was sufficient to drive both mouse and human embryonic stem cells to a differentiation-resistant, "hyper-pluripotent" state that readily reprogrammed to a primitive state resembling the preimplantation embryo
  • DDX6 influenced the fate of adult progenitors in a context-dependent manner: it promoted differentiation in neural progenitor cells and endoderm progenitors but maintained self-renewal and repressed differentiation in mesenchymal and muscle progenitors
  • When P-bodies were dissolved by loss of DDX6, mRNAs were released to translational machinery; increased protein levels of transcription and chromatin factors then potently influenced the fate of embryonic and adult stem cells

Interpretation

P-body assembly seems to confer a ''poised'' state on stem cells that may be reversed quickly upon reception of appropriate cues. This facilitates timely cell development and differentiation.

Tissue-based stem cell models will be critical for probing P-body function in vivo. Findings related to the stability of stem cell fate and identity are relevant to cancer research, in part to discover how to "reprogram" stem cells to change their fate in more targeted, therapeutically relevant ways.

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