Cross-talk between chromatin acetylation and SUMOylation of tripartite motif–containing protein 24 (TRIM24) impacts cell adhesion

Abstract

Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif-containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional cross-talk between histone acetylation and TRIM24 SUMOylation. Binding of TRIM24 to chromatin via its tandem PHD-bromodomain, which recognizes unmethylated lysine 4 and acetylated lysine 23 of histone H3 (H3K4me0/K23ac), led to TRIM24 SUMOylation at lysine residues 723 and 741. Inactivation of the bromodomain, either by mutation or with a small-molecule inhibitor, IACS-9571, abolished TRIM24 SUMOylation. Conversely, inhibition of histone deacetylation markedly increased TRIM24's interaction with chromatin and its SUMOylation. Of note, gene expression profiling of MCF7 cells expressing WT SUMO-deficient TRIM24 identified cell adhesion as the major pathway regulated by the cross-talk between chromatin acetylation and TRIM24 SUMOylation. In conclusion, our findings establish a new link between histone H3 acetylation and SUMOylation of the reader protein TRIM24, a functional connection that may bear on TRIM24's oncogenic function and may inform future studies of PTM cross-talk between histones and epigenetic regulators.

Milestones in transcription and chromatin published in the Journal of Biological Chemistry

“…Acetyl-lysine reader proteins, such as BRD4 and TRIM24, have received considerable attention due to their involvement in expression of MYC and other cancer-promoting oncogenes (91,92). BRD4 is a member of the bromodomain and extraterminal domain (BET) family and, as noted above, plays an important role in transcriptional elongation.…”

“…Studies such as this will certainly facilitate the development of BET inhibitors. Similarly, TRIM24 (tripartite motif-containing protein 24) is a reader of H3K23ac, and inhibitors are also being developed as anti-cancer agents (92).…”

“…Similar to studies with inhibitors of acetyl-lysine readers (91,92), both the histone lysine methyltransferases (KMT) and methylated histone readers have been the subject of anti-cancer drug development efforts (101,102). In one recent study, Coussens et al (101) used nucleosome substrates to screen compound libraries for inhibitors of the KMT NSD2, which is overexpressed or mutated in a variety of human cancers.…”

A histone reader becomes the readout

“…The installation of modifications on nonhistone proteins could be necessary for mediating normal biological activities of these proteins or alternatively amend their functions in response to developmental and environmental cues. In the current issue of JBC, Appikonda et al (4) shed new light on this critical but poorly understood component of the nuclear signaling network in their report that the chromatin associated transcription co-factor TRIM24 can be modified in a manner that depends on histone binding and that this modification leads to the regulation of a specific subset of genes. These data provide an exciting example of molecular cross-talk between histone acetylation and nonhistone protein SUMOyla-tion and pose new questions about the biological consequences of this PTM-dependent signaling cascade.…”

“…However, other modifications known to be abundantly present on histones have been far less explored on nonhistone proteins. The work by Appikonda et al (4) affords an exciting look at one of these other modifications and also reveals how recognition of an epigenetic mark by a chromatin regulator induces modifica-tion of the same regulator to alter gene expression programs. This finding adds to growing evidence that modifications of nonhistone chromatin-associated factors provide an additional intricate layer of regulation within chromatin signaling pathways, offers novel and potentially more specific means for disrupting these pathways in the treatment of disease, and provides further impetus to study nonhistone modifications of all kinds.…”