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https://www.readbyqxmd.com/read/29196562/the-role-of-bromodomain-and-extraterminal-motif-bet-proteins-in-chromatin-structure
#1
Sarah C Hsu, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins have been widely investigated for their roles in gene regulation and their potential as therapeutic targets in cancer. Pharmacologic BET inhibitors target the conserved bromodomain-acetyllysine interaction and do not distinguish between BRD2, BRD3, and BRD4. Thus, comparatively little is known regarding the distinct roles played by individual family members, as well as the underlying mechanisms that drive the transcriptional effects of BET inhibitors. Here we review studies regarding the contributions of BET proteins to genome structure and function, including recent work identifying a role for BRD2 as a component of functional and physical chromatin domain boundaries...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29180574/mir-126-5p-promotes-retinal-endothelial-cell-survival-through-setd5-regulatio-in-neurons
#2
Villain Gaëlle, Poissonnier Loïc, Noueihed Baraa, Bonfils Gaëlle, Rivera Jose Carlos, Chemtob Sylvain, Soncin Fabrice, Mattot Virginie
MicroRNAs are key regulators of angiogenesis, as illustrated by the vascular defects observed in miR-126-deficient animals. While the miR-126 duplex gives rise to two mature microRNAs (miR-126-3p and -5p), these defects were attributed to the loss of miR-126-3p while the role of miR-126-5p during normal angiogenesis in vivo remains unknown. Here, we show that miR-126-5p is expressed in endothelial but also by retinal ganglion cells (RGC) of the postnatal retina and participates in protecting endothelial cells from apoptosis during the establishment of the retinal vasculature...
November 27, 2017: Development
https://www.readbyqxmd.com/read/29170024/exploiting-a-water-network-to-achieve-enthalpy-driven-bromodomain-selective-bet-inhibitors
#3
William R Shadrick, Peter J Slavish, Sergio C Chai, Brett Waddell, Michele Connelly, Jonathan A Low, Cynthia Tallant, Brandon M Young, Nagakumar Bharatham, Stefan Knapp, Vincent A Boyd, Marie Morfouace, Martine F Roussel, Taosheng Chen, Richard E Lee, R Kiplin Guy, Anang A Shelat, Philip M Potter
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby...
November 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29149598/harnessing-bet-inhibitor-sensitivity-reveals-amigo2-as-a-melanoma-survival-gene
#4
Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A Davies, Christopher R Vakoc, Eva Hernando, Emily Bernstein
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#5
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al., 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al., 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29077715/protein-dynamics-and-structural-waters-in-bromodomains
#6
Xiaoxiao Zhang, Kai Chen, Yun-Dong Wu, Olaf Wiest
Bromodomains are epigenetic readers of acetylated lysines that are integral parts of histone tails. The 61 bromodomains in humans are structurally highly conserved but specifically bind to widely varying recognition motifs, suggesting that dynamic rather than static factors are responsible for recognition selectivity. To test this hypothesis, the dynamics of the binding sites and structural water molecules of four bromodomains (ATAD2, BAZ2B, BRD2(1) and CREBBP) representing four different subtypes is studied with 1 μs MD simulations using the RSFF2 force field...
2017: PloS One
https://www.readbyqxmd.com/read/29018219/spatially-restricted-loading-of-brd2-at-dna-double-strand-breaks-protects-h4-acetylation-domains-and-promotes-dna-repair
#7
Ozge Gursoy-Yuzugullu, Chelsea Carman, Brendan D Price
The n-terminal tail of histone H4 recruits repair proteins, including 53BP1, to DNA double-strand breaks (DSB) and undergoes dynamic acetylation during DSB repair. However, how H4 acetylation (H4Ac) recruits repair proteins and reorganizes chromatin during DNA repair is unclear. Here, we show that the bromodomain protein BRD2 is recruited to DSBs. This recruitment requires binding of BRD2's tandem bromodomains to H4Ac, which is generated at DSBs by the Tip60/KAT5 acetyltransferase. Binding of BRD2 to H4Ac protects the underlying acetylated chromatin from attack by histone deacetylases and allows acetylation to spread along the flanking chromatin...
October 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28983974/molecular-design-of-stat3-derived-peptide-selectivity-between-bet-proteins-brd2-and-brd4-in-ovarian-cancer
#8
Lixia Zhu, Xi Ding
Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide-medicated interaction of Stat3 with BET family members Brd2 and Brd4 -- 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCXYLGVA, QSKVLTXSYWGA, and RQCNLGXLYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3...
October 6, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28955774/unveiling-the-folding-mechanism-of-the-bromodomains
#9
Maria Petrosino, Daniela Bonetti, Alessandra Pasquo, Laura Lori, Roberta Chiaraluce, Valerio Consalvi, Carlo Travaglini-Allocatelli
Bromodomains (BRDs) are small protein domains often present in large multidomain proteins involved in transcriptional regulation in eukaryotic cells. They currently represent valuable targets for the development of inhibitors of aberrant transcriptional processes in a variety of human diseases. Here we report urea-induced equilibrium unfolding experiments monitored by circular dichroism (CD) and fluorescence on two structurally similar BRDs: BRD2(2) and BRD4(1), showing that BRD4(1) is more stable than BRD2(2)...
September 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28949335/the-bet-brd-inhibitor-jq1-improves-brain-plasticity-in-wt-and-app-mice
#10
E Benito, B Ramachandran, H Schroeder, G Schmidt, H Urbanke, S Burkhardt, V Capece, C Dean, A Fischer
Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease...
September 26, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28846108/runx3-plays-a-critical-role-in-restriction-point-and-defense-against-cellular-transformation
#11
X-Z Chi, J-W Lee, Y-S Lee, I Y Park, Y Ito, S-C Bae
The restriction (R)-point decision is fundamental to normal differentiation and the G1-S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context-dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3(-/-)mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3(-/-)MEFs and K-Ras-activated Runx3(-/-)MEFs (Runx3(-/-);K-Ras(G12D/+))...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28821780/selective-inhibition-mechanism-of-rvx-208-to-the-second-bromodomain-of-bromo-and-extraterminal-proteins-insight-from-microsecond-molecular-dynamics-simulations
#12
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#13
Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#14
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#15
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28737745/electromagnetized-gold-nanoparticles-mediate-direct-lineage-reprogramming-into-induced-dopamine-neurons-in-vivo-for-parkinson-s-disease-therapy
#16
Junsang Yoo, Euiyeon Lee, Hee Young Kim, Dong-Ho Youn, Junghyun Jung, Hongwon Kim, Yujung Chang, Wonwoong Lee, Jaein Shin, Soonbong Baek, Wonhee Jang, Won Jun, Soochan Kim, Jongki Hong, Hi-Joon Park, Christopher J Lengner, Sang Hyun Moh, Youngeun Kwon, Jongpil Kim
Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes...
October 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/28733670/brd3-and-brd4-bet-bromodomain-proteins-differentially-regulate-skeletal-myogenesis
#17
Thomas C Roberts, Usue Etxaniz, Alessandra Dall'Agnese, Shwu-Yuan Wu, Cheng-Ming Chiang, Paul E Brennan, Matthew J A Wood, Pier Lorenzo Puri
Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710461/bromodomain-factors-of-bet-family-are-new-essential-actors-of-pericentric-heterochromatin-transcriptional-activation-in-response-to-heat-shock
#18
Edwige Col, Neda Hoghoughi, Solenne Dufour, Jessica Penin, Sivan Koskas, Virginie Faure, Maria Ouzounova, Hector Hernandez-Vargash, Nicolas Reynoird, Sylvain Daujat, Eric Folco, Marc Vigneron, Robert Schneider, André Verdel, Saadi Khochbin, Zdenko Herceg, Cécile Caron, Claire Vourc'h
The heat shock response is characterized by the transcriptional activation of both hsp genes and noncoding and repeated satellite III DNA sequences located at pericentric heterochromatin. Both events are under the control of Heat Shock Factor I (HSF1). Here we show that under heat shock, HSF1 recruits major cellular acetyltransferases, GCN5, TIP60 and p300 to pericentric heterochromatin leading to a targeted hyperacetylation of pericentric chromatin. Redistribution of histone acetylation toward pericentric region in turn directs the recruitment of Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, BRD4, which are required for satellite III transcription by RNAP II...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696179/insights-into-the-crystal-structure-of-brd2-bd2-phenanthridinone-complex-and-theoretical-studies-on-phenanthridinone-analogs
#19
Shruti Mathur, Prashant Deshmukh, Shailesh Tripathi, Palaniappan Marimuthu, Balasundaram Padmanbhan
BET (Bromodomain and Extra-terminal) family proteins recognize the acetylated histone code on chromatin and participate in downstream processes like DNA replication, modification, and repair. As part of epigenetic approaches, BRD2 and BRD4 were identified as putative targets, for the management of chronic diseases. We have recently reported the discovery of a new scaffold of the phenanthridinone based inhibitor (L10) of the second bromodomain of BRD2 (BRD2-BD2). Here, we present the crystal structure of the BRD2-BD2, refined to 1...
July 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28636645/genetic-susceptibility-in-juvenile-myoclonic-epilepsy-systematic-review-of-genetic-association-studies
#20
REVIEW
Bruna Priscila Dos Santos, Chiara Rachel Maciel Marinho, Thalita Ewellyn Batista Sales Marques, Layanne Kelly Gomes Angelo, Maísa Vieira da Silva Malta, Marcelo Duzzioni, Olagide Wagner de Castro, João Pereira Leite, Fabiano Timbó Barbosa, Daniel Leite Góes Gitaí
BACKGROUND: Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies. METHODOLOGY: A systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality...
2017: PloS One
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