Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain

Abstract

Drosophila Polycomb (PC), a subunit of Polycomb repressive complex 1 (PRC1), is well known for its role in maintaining repression of the homeotic genes and many others and for its binding to trimethylated histone H3 on Lys 27 (H3K27me3) via its chromodomain. Here, we identify a novel activity of PC: inhibition of the histone acetylation activity of CREB-binding protein (CBP). We show that PC and its mammalian CBX orthologs interact directly with the histone acetyltransferase (HAT) domain of CBP, binding to the previously identified autoregulatory loop, whose autoacetylation greatly enhances HAT activity. We identify a conserved PC motif adjacent to the chromodomain required for CBP binding and show that PC binding inhibits acetylation of histone H3. CBP autoacetylation impairs PC binding in vitro, and PC is preferentially associated with unacetylated CBP in vivo. PC knockdown elevates the acetylated H3K27 (H3K27ac) level globally and at promoter regions of some genes that are bound by both PC and CBP. Conversely, PC overexpression decreases the H3K27ac level in vivo and also suppresses CBP-dependent Polycomb phenotypes caused by overexpression of Trithorax, an antagonist of Polycomb silencing. We find that PC is physically associated with the initiating form of RNA polymerase II (Pol II) and that many promoters co-occupied by PC and CBP are associated with paused Pol II, suggesting that PC may play a role in Pol II pausing. These results suggest that PC/PRC1 inhibition of CBP HAT activity plays a role in regulating transcription of both repressed and active PC-regulated genes.Polycomb | CBP | acetylation | histone H3K27 | Drosophila

Dynamics of RNA Polymerase II Pausing and Bivalent Histone H3 Methylation during Neuronal Differentiation in Brain Development

“…Interestingly, our data revealed that H3K27me3 was positively correlated with Pol II-Ser5P in both NPCs and neurons. In this regard, it is intriguing to note that Drosophila PRC (Polycomb-repressive complex) could physically interact with paused Pol II (Tie et al, 2016) and was preferentially localized to paused promoters (Enderle et al, 2011). In addition, between the two classes of bivalent domains in embryonic stem cells (Ku et al, 2008), it was found that promoters bound by PRC2 alone could allow Pol II pausing (Min et al, 2011), although PRC1 and PRC2 co-occupied promoters were devoid of paused Pol II.…”

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…In addition, PcG proteins bind directly to the acetyltransferase CREB-binding protein (CBP), and inhibit its catalytic activity towards H3K27 [43]. Together, these events maintain local chromatin compaction precluding the transcription of target genes (Figure 2A).…”

How Polycomb‐Mediated Cell Memory Deals With a Changing Environment

“…Mouse postnatal cardiomyocites display Eed interaction with HDACs, enhancing their catalytic activity; this novel Eed function is an H3K27me3 independent repressive mechanism, crucial for physiological heart function . Similarly in Drosophila, Pc has been demonstrated to interact with the CREB‐binding protein (CBP) acetyl transferase, inhibiting its histone acetyltransferase activity …”