BROMODOMAINS IN CANCER AND INFLAMMATION

The PBRM1 protein, a key component of the PBAF chromatin remodeling complex, contains six bromodomains that recognize acetylated lysine residues on histones, linking epigenetic modifications to gene regulation and chromatin accessibility. As a tumor suppressor, PBRM1 is frequently mutated in cancers, especially clear cell renal cell carcinoma (ccRCC). There, many mutations cluster in its bromodomain, particularly the fourth (BD4). While many mutations cause complete loss of PBRM1 expression, about 15% are missense mutations that result in full-length proteins with potentially altered function. In Bursch et al (2024), we used computational, biophysical, and cellular methods to analyze 16 cancer-associated BD4 missense variants. PBRM1 mutations differentially affect protein stability, binding to acetylated histones, and tumor suppressor functions. These findings underscore the functional diversity of PBRM1 mutations and their potential impact on cancer progression and response to therapies like immune checkpoint blockade, highlighting the need for deeper characterization to inform precision medicine strategies.

Macrophages may regulate inflammation through lysine lactylation (Kla), a novel histone modification. Lysine lactylation arises from the metabolic byproduct lactate and builds up in inflammatory (M1) macrophages during the later stages of their activation. It also may help silence inflammation-promoting genes. The Smith Lab screened bromodomain-containing proteins, which are typically known for binding lysine acetylation, for Kla binding (Nuñez et al, 2024). TRIM33 was the only protein identified in this screen with a binding affinity for Kla, an interaction confirmed in a cellular context by immunoprecipitation. These findings reveal TRIM33 as the first known bromodomain-containing "reader" of histone Kla, shedding light on how metabolism can influence gene regulation during inflammation and offering new potential targets for treating inflammatory diseases.

Despite clear implications in numerous inflammation-related diseases, such as cancer, diabetes, and heart disease, much remains unknown regarding bromodomain structure, function, and potential drug targets. We approach these unknowns using methodology developed in the MCW Program in Chemical Biology and Mellowes Center Structural Genomics Unit. We develop novel inhibitors and chemical probes, and investigate disease-associated mutations.

Bromodomain proteins are known as epigenetic "readers," and their role in binding to acetylated lysine residues on histone proteins is well-described. However, since 1963, when lysine acetylation was first described, numerous distinct acylation marks on lysines have been recently discovered. Levels of different acylated-CoA species can be linked to the metabolome, thus posing a potential link between metabolism and regulation of transcription by bromodomain binding. We seek to understand the significance of bromodomain protein interactions with the broad range of acylations and the downstream effects on transcriptional regulation.