Transcriptional activation of polycomb-repressed genes by ZRF1

Abstract

Covalent modification of histones is fundamental in orchestrating chromatin dynamics and transcription. One example of such an epigenetic mark is the mono-ubiquitination of histones, which mainly occurs at histone H2A and H2B. Ubiquitination of histone H2A has been implicated in polycomb-mediated transcriptional silencing. However, the precise role of the ubiquitin mark during silencing is still elusive. Here we show in human cell lines that ZRF1 (zuotin-related factor 1) is specifically recruited to histone H2A when it is ubiquitinated at Lys 119 by means of a novel ubiquitin-interacting domain that is located in the evolutionarily conserved zuotin domain. At the onset of differentiation, ZRF1 specifically displaces polycomb-repressive complex 1 (PRC1) from chromatin and facilitates transcriptional activation. A genome-wide mapping of ZRF1, RING1B and H2A-ubiquitin targets revealed its involvement in the regulation of a large set of polycomb target genes, emphasizing the key role ZRF1 has in cell fate decisions. We provide here a model of the molecular mechanism of switching polycomb-repressed genes to an active state.

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

“…In shZrf1 cells we noted stabilization of Ring1b at chromatin in agreement with our previous findings. 18 Med12 levels at chromatin remained unaltered but recruitment of Cdk8 was drastically impaired in Zrf1 knockdown cells. Importantly, knockdown of Zrf1 has no impact on the mRNA and the protein levels of Cdk8 (Figs.…”

“…5F) is reminiscent of the function of Zrf1, which displaces PRC1 from chromatin to derepress Polycomb target genes. 18 To verify whether Zrf1 activates developmental target genes repressed by Med12 and Ring1b, we analyzed Zrf1 knockdown cells after stimulation with RA. We found that transcriptional activation of selected Med12-Ring1b target genes was dramatically impaired in shZrf1 cells (Fig.…”

“…[14][15][16][17] PRC1 is dislocated from chromatin by Zrf1, which tethers to H2AK119ub via a specific ubiquitin-binding domain. 18 Hence, PRC1-mediated ubiquitylation of H2A is a prerequisite for Zrf1 recruitment and thereby PRC1 dislocation. In higher eukaryotes, the carboxy-terminus of Zrf1 harbors 2 SANT domains, which are thought to directly interact with DNA.…”

Histone Monoubiquitylation Position Determines Specificity and Direction of Enzymatic Cross-talk with Histone Methyltransferases Dot1L and PRC2

“…Finally, Richly et al (40) identified ZRF1 as an H2Aub-binding protein involved in differentiation-dependent transcriptional activation of Polycomb target genes. If reduced PRC2 activity on Polycomb group-repressed genes is an important early step in pushing the chromatin state toward one more permissive to transcription, then our in vitro cross-talk data may provide another layer of mechanistic explanation for H2Aub involvement in transcriptional derepression.…”

The flip side of the coin: Role of ZRF1 and histone H2A ubiquitination in transcriptional activation

“…1 Our results suggest that ZRF1 exerts its function in a two-step mechanism, by initially displacing the Polycomb-repressive complex 1 (PRC1) from chromatin and subsequently acting together with histone H2A-specific deubiquitinases to facilitate transcriptional activation of its target genes. These findings demonstrate an ambiguity of the epigenetic monoubiquitin mark at histone H2A.…”