Polycomb recruitment to DNA in vivo by the YY1 REPO domain

Abstract

Polycomb group (PcG) proteins are responsible for maintaining transcriptional repression of developmentally important genes. However, the mechanism of PcG recruitment to specific DNA sequences is poorly understood. Transcription factor YY1 is one of the few PcG proteins with sequence-specific DNA binding activity. We previously showed that YY1 can recruit other PcG proteins to DNA, leading to histone posttranslational modifications and stable transcriptional repression. Using Drosophila transgenic approaches, we identified YY1 sequences 201-226 as necessary and sufficient for PcG transcriptional repression in vivo. When fused to a heterologous DNA-binding domain, this short 26-aa motif was sufficient for transcriptional repression, recruitment of PcG proteins to DNA, and methylation of histone H3 lysine 27. Deletion of this short YY1 motif did not affect transient transcriptional repression but ablated PcG repression, PcG protein recruitment to DNA, and methylation of H3 lysine 27. We propose that this motif be named the REPO domain for its function in recruitment of Polycomb. The REPO domain is well conserved in YY1 orthologs and in related proteins.repression ͉ transcription ͉ chromatin P olycomb group (PcG) proteins are responsible for the heritable silencing of target genes in metazoans (1, 2) and are functionally conserved in Drosophila and mammals (2, 3). Mutations in PcG genes result in misexpression of target genes with resulting homeotic transformation of body parts (4). Studies in mammals showed that PcG proteins are important for normal skeletal, muscular, and hematopoietic development (5). A variety of studies support the existence of at least two PcG complexes, each composed of several polypeptides: PRC1, containing Polycomb (Pc), polyhomeotic (Ph), dRing, and posterior sex combs (Psc); and PRC2 containing enhancer of zeste [E(z)], extra sex combs (Esc), and suppressor of zeste 12 [Su(z)12] (1, 2). These complexes are recruited to chromatin, where they maintain transcriptional silencing. An unresolved issue is the mechanism of recruitment of PcG complexes to appropriate target genes.The mechanism of PcG complex recruitment has remained elusive, especially in mammals. Drosophila Polycomb response elements (PREs) bind to PcG proteins and silence cis-linked genes in vivo (1, 2). The large size and poor sequence homology of characterized PREs has hampered the search for recruiting factors. Furthermore, nearly all characterized PcG proteins lack sequencespecific DNA-binding activity. Exceptions include the Drosophila PcG proteins Pleiohomeotic (PHO) and Pleiohomeotic-like (PHOL) and their mammalian counterpart, the vertebrate transcription factor Yin Yang 1 (YY1) (6, 7). Homology between these transcription factors is localized to the C-terminal zinc-finger DNA-binding domain (YY1 residues 298-414, 95% identical to PHO) and a short internal sequence (YY1 residues 205-226, 82% identical to PHO). We previously demonstrated that, similar to PHO, YY1 can function as a PcG protein to mediate silencing (8). Th...

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“…The N terminus has been implicated in transcriptional activation, whereas residues 170 -201 participate in transcriptional repression (12,13). Residues 201-226 form the REPO (recruitment of polycomb) domain, involved in polycomb group repression (14).…”

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