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Stem Cell Biology, Molecular & Cellular Biology, Disease Mechanisms

Changes in housekeeping functions drive stem cell differentiation

Cells acquire distinct fates and functions during development. A study from IMBA reveals a new mechanism of cell fate specification involving the regulation of cell metabolism.

Our bodies contain hundreds of distinct cell types. We know that transcription factors can turn on specific gene sets to direct cell fate specification. Now, researchers from IMBA- the Institute of Molecular Biotechnology – report that also changes in splicing and protein synthesis, two basic cellular processes known for their housekeeping function, can control differentiation and development.

The Knoblich lab has previously demonstrated that the conserved RNA binding protein Barricade is required to specify the neural lineage in fruit flies. They now show that its homolog HTATSF1 is required for embryonic development in mice. HTATSF1 is necessary for maintaining mouse embryonic stem cells (mESC) in a pluripotent state where they can give rise to multiple cell types - whereas mESCs overexpressing HTATSF1 fail to differentiate. Consistent with these findings, HTATSF1 levels decrease during differentiation of mESCs and embryonic development.

Knoblich’s group found that HTATSF1 regulates ribosome levels. Specifically, HTATSF1 is required for proper expression and processing of ribosomal RNAs, and for normal splicing of a subset of messenger RNAs that encode ribosomal proteins. As a result, ribosome numbers and protein synthesis rates are reduced in mESCs lacking HTATSF1, as they are in differentiating mESCs and developing mouse embryos. Importantly, restoring protein synthesis in HTATSF1 mutant mESCs also restores pluripotency.

These findings support the emerging concept that „housekeeping functions“ can be regulated to direct cell fate. “Our results show that the coordinated regulation of mRNAs encoding ribosomal proteins and rRNAs influences protein synthesis to control embryonic stem cell maintenance and differentiation,” says Nina Corsini, first author of the current publication in Cell Stem Cell, and Postdoc in the Knoblich lab. These findings may have clinical implications for diseases caused by altered ribosome biogenesis, including cancer and „ribosomopathies“ like Diamond Blackfan Anemia.