TRIM24 links a non-canonical histone signature to breast cancer

Abstract

Recognition of modified histone species by distinct structural domains within “reader” proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here, we report that chromatin regulator TRIM24 functions as a reader of dual histone marks via tandem Plant Homeodomain (PHD) and Bromodomain (Bromo). The three-dimensional structure of TRIM24 PHD-Bromo revealed a single functional unit for combinatorial recognition of unmodified H3K4 (H3K4me0) and acetylated H3K23 (H3K23ac) within the same histone tail. TRIM24 binds chromatin and estrogen receptor to activate estrogen-dependent genes associated with cellular proliferation and tumor development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation via a noncanonical histone signature, establishing a new paradigm by which chromatin readers may influence cancer pathogenesis.

The bromodomain interaction module

“…The BRD of ATAD2 has been shown to immunoprecipitate histone H3 (K14 ac [68]) but this interaction has not been quantified yet, while the closely homologous KIAA1240 binds to histone H4 (K5 ac [33,69] [70]). Subfamily V of the human BRDs contains the transcriptional repressor tripartite motif-containing 66 (TRIM66) [71], the tripartite motif-containing 33 (TRIM33) [72], the transcriptional regulator transcriptional intermediary factor 1 (TIF1a) [73], the transcriptional regulators nuclear auto-antigen Sp-100 (SP100) [74], nuclear autoantigen Sp-110 (SP110) [75] and SP140 nuclear body protein (SP140) [76] as well as the SP140-like protein (LOC93349), the transcriptional repressor bromodomain adjacent to zinc finger domain 2A (BAZ2A) [77] and the bromodomain adjacent to zinc finger domain 2B (BAZ2B) [78]. The main characteristic of this sub-class of bromodomains is the existence of a PHD/BRD tandem module which seems to be a necessary structural motif for peptide recognition as well as protein stability [73,79].…”

“…Subfamily V of the human BRDs contains the transcriptional repressor tripartite motif-containing 66 (TRIM66) [71], the tripartite motif-containing 33 (TRIM33) [72], the transcriptional regulator transcriptional intermediary factor 1 (TIF1a) [73], the transcriptional regulators nuclear auto-antigen Sp-100 (SP100) [74], nuclear autoantigen Sp-110 (SP110) [75] and SP140 nuclear body protein (SP140) [76] as well as the SP140-like protein (LOC93349), the transcriptional repressor bromodomain adjacent to zinc finger domain 2A (BAZ2A) [77] and the bromodomain adjacent to zinc finger domain 2B (BAZ2B) [78]. The main characteristic of this sub-class of bromodomains is the existence of a PHD/BRD tandem module which seems to be a necessary structural motif for peptide recognition as well as protein stability [73,79]. The BRD of TIF1a binds acetylated histone H3 peptides with weak micromolar affinity which is enhanced when longer peptides and the tandem PHD/BRD module are used, suggesting a cooperativity between modules even though peptides may not be methylated in order to promote binding to the PHD finger [73].…”

“…The main characteristic of this sub-class of bromodomains is the existence of a PHD/BRD tandem module which seems to be a necessary structural motif for peptide recognition as well as protein stability [73,79]. The BRD of TIF1a binds acetylated histone H3 peptides with weak micromolar affinity which is enhanced when longer peptides and the tandem PHD/BRD module are used, suggesting a cooperativity between modules even though peptides may not be methylated in order to promote binding to the PHD finger [73]. It is noteworthy that a monoacetylated histone H3 peptide (K23 ac ) spanning residues 1-28 binds with double digit nM affinity to the PHD/BRD tandem module of TIF1a.…”

TRIM24 promotes the aggression of gastric cancer via the Wnt/β-catenin signaling pathway

“…The aberrant overexpression of TRIM24 is a prognostic factor in several types of cancer, and promotes tumor development and progression through various mechanisms. TRIM24 ubiquitinates and induces the proteasome-mediated degradation of p53 (11,12), and can also bind to chromatin and the estrogen receptor to activate target genes associated with cell proliferation and tumor development in breast cancer (13). TRIM24 also promotes tumorigenesis by activating aerobic glycolysis (14) and serves as a target of chromosomal translocations leading to the formation of oncogenic fusion proteins (15)(16)(17).…”

Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma

“…Members of this subfamily share a common N-terminal TRIM previously known as a RING-Bbox-coiled-coil (RBCC) motif and a chromatin binding unit comprising a C-terminal plant homeo domain finger and bromodomain that act as a single functional unit to promote recognition of a combination of unmethylated lysine 4 of histone H3 (H3K4me0) and acetylated H3K23 (23). Tripartite motif 28 (TRIM28) [transcriptional intermediary factor 1 beta (TIF1β), KRAB-associated protein 1 (KAP1)] possesses an intrinsic silencing activity and also acts through chromatin via recruitment of chromatin modifiers (24)(25)(26)(27)(28).…”