A histone reader becomes the readout

Abstract

Chromatin signaling events are critical for the dynamic regulation of the genome. Although much has been learned about histone modification in these events, the modification of nonhistone chromatin regulators and cross-talk between these pathways is less well understood. Here, Appikonda et al. demonstrate that the transcription co-factor and oncoprotein TRIM24 (tripartite motif–containing protein 24) is SUMOylated upon association with a specific histone modification signature, which regulates the transcription of genes involved in cell adhesion. These data extend our understanding of signaling cascades in the nucleus and offer new insights for cancer drug development.

Introduction

A wide array of nuclear processes depend on chemical modification of chromatin components that are coupled with changes in chromatin structure and/or gene regulation. A plethora of histone post-translational modifications (PTMs)³ and several DNA modifications, together referred to as epigenetic marks, have been identified over the past few years. In addition, a multifaceted cellular machinery for placing and removing these modifications has been identified and experimentally characterized for some of these marks (1–3). Whereas histones and DNA have been the primary focus of attention, this same machinery also has the potential capacity to target nuclear nonhistone proteins. 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 SUMOylation and pose new questions about the biological consequences of this PTM-dependent signaling cascade.

TRIM24 is a multifunctional chromatin regulator and an E3-ubiquitin ligase known to associate with a number of nuclear receptors such as the estrogen receptor α. The C-terminal region of TRIM24 contains the tandem PHD finger domain and bromodomain (BD) that were previously shown by the Barton and Patel groups to bind the histone H3 tail (5). In particular, the PHD-BD module was found to specifically recognize the dual modification state, unmodified H3K4 and acetylated H3K23 (H3K4me0/H3K23ac). This bivalent readout can promote the recruitment of TRIM24 to, or stabilize this protein at H3K23ac-enriched chromatin. But what are the far-reaching functional consequences of this interaction?

Using a combination of cellular and in vitro assays, Appikonda et al. (4) now show that the PHD-BD binding event induces TRIM24 SUMOylation at two lysine residues which lie N-terminal to the PHD-BD module (Fig. 1). The authors further demonstrate that SUMOylated TRIM24 differentially alters gene expression as compared with unmodified TRIM24, up-regulating a subset of genes primarily important for cell adhesion. Finally, the authors confirm that cells containing TRIM24 mutants incapable of being SUMOylated display reduced binding to several extracellular matrix proteins.

Figure 1.

Functional cross-talk between histone acetylation and nonhistone protein TRIM24 SUMOylation. Binding of the tandem PHD-BD module of TRIM24 to the epigenetic mark H3K23ac (1) promotes SUMOylation of TRIM24 at two sites, Lys⁷²³ and Lys⁷⁴¹ (2), which subsequently leads to transcriptional regulation of genes involved in cell adhesion pathways (3). TRIM24 has previously been shown to promote malignant transformation, and the new findings reported here suggest a novel link between the ability of TRIM24 to recognize H3K23ac and undergo SUMOylation and its oncogenic activity. The tripartite motif (ring, B-Box and coiled-coil; RBCC) of TRIM24 is also shown.

Dysregulation of histone PTM signaling is known to be linked to a broad range of diseases, and associated proteins have emerged as promising drug targets (6). Likewise, dysregulation of modifications on nuclear nonhistone proteins may result in aberrant activities, providing new therapeutic avenues. TRIM24 is an oncoprotein overexpressed in many human malignancies, and its aberrant up-regulation in breast cancer was found to correlate with poor survival prognosis (5, 7, 8). Depletion of TRIM24 results in decreased proliferation and survival of tumor-derived breast cancer cells. Multiple mechanisms by which TRIM24 promotes tumorigenic programs have been proposed and studied (9). These include TRIM24 translocations and formation of oncogenic fusion proteins, TRIM24-mediated ubiquitination of p53, and TRIM24-dependent activation of estrogen receptor α that, in turn, stimulates expression of proliferation factors. Collectively, a wealth of research observations suggests that TRIM24 is an attractive therapeutic target in multiple cancers. The novel regulatory pathway discovered by Appikonda et al. (4) may help to explain the neoplastic cell transformation observed when TRIM24 is aberrantly expressed. Specifically, the authors show that TRIM24 SUMOylation regulates the expression of genes required for cell adhesion and is necessary for proper association of cancer cells with extra cellular matrix proteins. As cell adhesion is essential in cell proliferation, migration, and metastasis, the findings by the Barton group (4) offer an appealing new avenue in exploring the potential of TRIM24 as an anti-cancer drug target or diagnostic biomarker.

Among various modifications, nonhistone acetylation and methylation have been the focus of most studies in the past several years, with a number of target sites being identified and tools actively being developed for further discovery (10). 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 modification 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. Let the reader become the readout!