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Opportunity knocks for uncovering the new function of an understudied nucleosome remodeling complex member, the bromodomain PHD finger transcription factor, BPTF.

ABSTRACT: Nucleosome remodeling provides access to genomic DNA for recruitment of the transcriptional machinery to mediate gene expression. The aberrant function of nucleosome remodeling complexes has been correlated to human cancer, making them emerging therapeutic targets. The bromodomain PHD finger transcription factor, BPTF, is the largest member of the human nucleosome remodeling factor NURF. Over the last five years, BPTF has become increasingly identified as a protumorigenic factor, prompting investigations into the molecular mechanisms associated with BPTF function. Despite a druggable bromodomain, small molecule discovery is at an early stage. Here we highlight recent investigations into the biology being discovered for BPTF, chemical biology approaches used to study its function, and small molecule inhibitors being designed as future chemical probes and therapeutics.

SUBMITTER: Zahid H

PROVIDER: S-EPMC8384639 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Opportunity knocks for uncovering the new function of an understudied nucleosome remodeling complex member, the bromodomain PHD finger transcription factor, BPTF.

Zahid Huda H Olson Noelle M NM Pomerantz William C K WCK

Current opinion in chemical biology 20210308

Nucleosome remodeling provides access to genomic DNA for recruitment of the transcriptional machinery to mediate gene expression. The aberrant function of nucleosome remodeling complexes has been correlated to human cancer, making them emerging therapeutic targets. The bromodomain PHD finger transcription factor, BPTF, is the largest member of the human nucleosome remodeling factor NURF. Over the last five years, BPTF has become increasingly identified as a protumorigenic factor, prompting inves ...[more]

PMID: 33706239

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Project description:Mono-, di- and trimethylated states of particular histone lysine residues are selectively found in different regions of chromatin, thereby implying specialized biological functions for these marks ranging from heterochromatin formation to X-chromosome inactivation and transcriptional regulation. A major challenge in chromatin biology has centred on efforts to define the connection between specific methylation states and distinct biological read-outs impacting on function. For example, histone H3 trimethylated at lysine 4 (H3K4me3) is associated with transcription start sites of active genes, but the molecular 'effectors' involved in specific recognition of H3K4me3 tails remain poorly understood. Here we demonstrate the molecular basis for specific recognition of H3(1-15)K4me3 (residues 1-15 of histone H3 trimethylated at K4) by a plant homeodomain (PHD) finger of human BPTF (bromodomain and PHD domain transcription factor), the largest subunit of the ATP-dependent chromatin-remodelling complex, NURF (nucleosome remodelling factor). We report on crystallographic and NMR structures of the bromodomain-proximal PHD finger of BPTF in free and H3(1-15)K4me3-bound states. H3(1-15)K4me3 interacts through anti-parallel beta-sheet formation on the surface of the PHD finger, with the long side chains of arginine 2 (R2) and K4me3 fitting snugly in adjacent pre-formed surface pockets, and bracketing an invariant tryptophan. The observed stapling role by non-adjacent R2 and K4me3 provides a molecular explanation for H3K4me3 site specificity. Binding studies establish that the BPTF PHD finger exhibits a modest preference for K4me3- over K4me2-containing H3 peptides, and discriminates against monomethylated and unmodified counterparts. Furthermore, we identified key specificity-determining residues from binding studies of H3(1-15)K4me3 with PHD finger point mutants. Our findings call attention to the PHD finger as a previously uncharacterized chromatin-binding module found in a large number of chromatin-associated proteins.

Dataset Information

Opportunity knocks for uncovering the new function of an understudied nucleosome remodeling complex member, the bromodomain PHD finger transcription factor, BPTF.

Publications

Opportunity knocks for uncovering the new function of an understudied nucleosome remodeling complex member, the bromodomain PHD finger transcription factor, BPTF.

Similar Datasets

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