Stem Cell Differentiation Depends on Epigenetic Gene Silencing

A recent paper described the results of experiments designed to help explain the mechanistic basis for gene expression and silencing especially as it relates to stem cell differentiation.

Investigators at the University of North Carolina (Chapel Hill, USA) examined the role of the polycomb-like proteins (PCLs) as related to epigenetic gene silencing.

Polycomb-like proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. PRC1 and PRC2 (Polycomb Repressive Complex 2) comprise the two classes of PCLs. This complex has histone methyltransferase activity and primarily trimethylates histone H3 on lysine 27 (i.e. H3K27me3), which transcriptionally silences this region of chromatin. PRC2 is required for initial targeting of the genomic region (PRC Response Elements or PRE) to be silenced, while PRC1 is required for stabilizing this silencing and underlies cellular memory of silenced region after cellular differentiation. These proteins, which are present in all multicellular organisms, are required for long term epigenetic silencing of chromatin and have an important role in stem cell differentiation and early embryonic development.

The investigators reported in the December 27, 2012, online edition of the journal Molecular Cell that they had identified the coexistence of H3K36me3, H3K27me3, and PHF19/PCL3 at a subset of poised developmental genes in mouse pluripotent stem cells and demonstrated that PHF19/PCL3 Tudor function was required for optimal repression of these loci. The Tudor domain is an approximately 60-amino acid structure motif that is found in many chromatin proteins, where it mediates interactions with histones (and other proteins), often through binding specific methylated residues. PCL recognition of H3K36me3 promoted intrusion of PRC2 complexes into active chromatin regions to promote gene silencing and modulated the chromatin landscape during development.

"This finding has important implications for both stem cell biology and cancer development, as the same regulatory circuits controlled by PCLs in stem cells are often misregulated in tumors," said senior author Dr. Greg Wang, assistant professor of biochemistry and biophysics at the University of North Carolina. "The identification of a specific PCL in controlling PRC2 in cancer cells suggests we may be able to develop drugs targeting this PCL to regulate PRC2 function in a more controlled manner that may maintain PRC2 function in stem cells while inhibiting it in the tumor."

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