About this Research Topic
The BET (bromodomain and extra terminal) protein family includes four members, ubiquitously expressed Bromodomain2 (BRD2), BRD3, and BRD4 and testis-specific BRDT. Multifunctional BET family members act as epigenetic readers, histone chaperones, nucleosome disrupters and transcription factors, thus helping bridge dynamic changes in chromatin architecture with transcription. Despite having only four members, this family has an enormous interactome and dominates the nuclear landscape with multiple nuclear functions. These functions include the transmission of epigenetic memory across cell divisions, DNA damage response, modulation of RNAPII activity, and regulation of alternative splicing. A key function of BET proteins is to regulate c-MYC oncogene transcription, leading to increased cancer pathogenesis. Thus, targeting the BET-MYC axis has received tremendous attention over the last decade and the tools developed in the process have led to exciting new discoveries in many other diseases besides cancer. Going forward, a greater understanding of the molecular functions of BET proteins will be critical given the large number of therapeutic agents being currently developed to inhibit or degrade BET proteins.
The high sequence similarity and shared features of the BET family members leads to challenges when attempting to understand their mechanistic differences and molecular functions. First-generation drugs targeting the bromodomains of BET proteins were unable to discriminate between distinct BET proteins and were later referred to as pan-BET inhibitors. With the recent development of protein-targeting chimeras (PROTAC) and other targeted degradation systems, it is now possible to target otherwise essential individual BET proteins. These targeted degradation systems make it feasible to explore underestimated and undetermined functions of individual BET members without off-target perturbation. Additionally, exploration of individual BET protein interactomes by systematic proteomics will help enrich our knowledge of BET protein partners and the role these interactions play in regulating molecular mechanisms that govern chromatin architecture and transcription. Identifying such interactions will also open new avenues for targeting individual BET interactions, such as the BRD4-MYC or BRD4-NUT complexes, that play key roles in various cancers. Therefore, a major goal of this Research Topic is to increase the understanding of, and discover new, functions regulated by BET family members.
In this Research Topic we aim to collect studies addressing the biochemical basis of cellular functions of BET proteins. We encourage in vitro, in vivo, in silico, in situ, genomics, proteomics, and imaging approaches to mimic biological systems in order to understand BET biology. We welcome original research articles and reviews (including mini reviews) covering the following areas:
• Novel findings of distinct nuclear functions of BET proteins in different cell types
• Mechanistic understanding of functional differences between BET members
• Studies expanding the BET interaction repertoire
• Incorporation of in silico, in vitro, and in vivo approaches to uncover BET protein functions
• Protein Biochemistry, microscopy, biophysics and genomic approaches to address important biological questions related to BET proteins
• BET proteins in RNA biology
The illustration for this Research Topic was created by Anusree Dey (Molecular Biology Division, Bhabha Atomic Research Centre, India).
Keywords: BET proteins, Transcription, Cancer, chromatin architecture, BET inhibitors
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