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

Zahid, Huda; Olson, Noelle M.; Pomerantz, William C. K.

doi:10.1016/j.cbpa.2021.02.003

Cited by 16 publications

(15 citation statements)

References 73 publications

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“…The BPTF subunit is important for chromatin association of the NURF ( Nu cleosome R emodeling F actor) complex 27,28 , and is a pro-tumorigenic factor in several malignancies 29 . At the BPTF C-terminus is a tandem of reader domains: a PHD finger and bromodomain (PHD-BD, Fig.…”

Section: Bptf Phd-bd Demonstrates Restricted Specificity and Synergis...mentioning

confidence: 99%

Nucleosome conformation dictates the histone code

Marunde

Fuchs

Burg

et al. 2022

Preprint

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Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized "codes" that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order factors. Here we show that CAP-histone PTM interaction is in fact dependent on nucleosome context. Our results indicate this is due to histone tail accessibility and the associated impact on binding potential of reader domains. We further demonstrate that the in vitro specificity of a tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. This necessitates we refine the "histone code" concept and interrogate it at the nucleosome level.

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Section: Bptf Phd-bd Demonstrates Restricted Specificity and Synergis...mentioning

confidence: 99%

Nucleosome conformation dictates the histone code

Marunde

Fuchs

Burg

et al. 2022

Preprint

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“…1 H NMR (500 MHz, methanol-d 4 ) δ 7.49 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.59 (s, 1H), 3.70 (s, 3H). 13 4-Chloro-5-((4-fluorophenyl)amino)-2-methylpyridazin-3(2H)one (8). Following step 1 of the general procedure A (4,5-dichloro-2methylpyridazin-3(2H)-one (532 mg, 2.97 mmol, 1.1 equiv), 4fluoroaniline (300 mg, 2.70 mmol, 1.0 equiv), and N,N-diisopropylethylamine (940 μL, 5.40 mmol, 2.0 equiv)), product 8 was obtained as a white solid (52 mg, 8% yield over two steps).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Nucleosome remodeling factor (NURF) is one member of the ISWI family, consisting of an ATPase domain SNF2L, a WD-repeat protein RbAP46/48, and a chromatin-binding protein BPTF (Figure A) . Chemical probe development for these complex members remains at an early stage …”

Section: Introductionmentioning

confidence: 99%

“…7 Chemical probe development for these complex members remains at an early stage. 8 BPTF (bromodomain PHD finger transcription factor) is the largest subunit of NURF and is considered essential for its function. 9 BPTF contains a bromodomain, two PHD fingers, a DNA-association domain, three nuclear receptor binding motifs, and a glutamine-rich domain.…”

Section: ■ Introductionmentioning

confidence: 99%

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New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition

et al. 2021

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The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains. Here we describe the development of pyridazinone-based BPTF inhibitors. The lead compound, BZ1, possesses a high potency (K d = 6.3 nM) and >350-fold selectivity over BET bromodomains. We identify an acidic triad in the binding pocket to guide future designs. We show that our inhibitors sensitize 4T1 breast cancer cells to doxorubicin but not BPTF knockdown cells, suggesting a specificity to BPTF. Given the high potency and good physicochemical properties of these inhibitors, we anticipate that they will be useful starting points for chemical tool development to explore the biological roles of BPTF.

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“…The knockdown or inactivity of BPTF caused down-regulation of Cdc25A expression, while Cdc25A overexpression partially reversed the decreased proliferative capacity, cell cycle progression and subcutaneous xenograft growth of CRC cells mediated by BPTF silencing. In regard to the common role of BPTF as a transcriptional factor [ 9 , 49 ], we explored and verified the transcriptional regulation of BPTF on Cdc25A by anchoring at Cdc25A promoter region (−178-+107). Meanwhile, the upstream regulator of BPTF, c-Myc, was deduced and approved further in our study.…”

Section: Discussionmentioning

confidence: 99%