Beating the odds: BETs in disease

Wang, Chenyi; Filippakopoulos, P.

doi:10.1016/j.tibs.2015.06.002

Cited by 135 publications

(135 citation statements)

References 116 publications

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“…66,67 In aggregate, we propose that haploinsufficiency of BPTF results in an augmented neuronal death, which likely occurs mainly during the postnatal period and manifests with acquired microcephaly and neurodevelopmental abnormalities. Characteristic facial features involving nose and eyes as well as anomalies involving fingers and toes, resembling those reported in patients with 17q24.2 deletions, [68][69][70][71][72] enabled us to define a novel syndromic disorder.…”

Section: Discussionmentioning

confidence: 93%

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Stankiewicz

Khan

Szafrański

et al. 2017

The American Journal of Human Genetics

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Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

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Section: Discussionmentioning

confidence: 93%

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Stankiewicz

Khan

Szafrański

et al. 2017

The American Journal of Human Genetics

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“…4 Accordingly, many studies have focused on how BRD4 is involved in different diseases, in particular cancer. 5 In a recent manuscript, Sakamaki et al revealed a previously unidentified transcriptional role of BRD4 in negatively regulating several autophagy and lysosome genes, thereby modulating autophagy and lysosome functions. 6 Initially, the authors conducted an RNAi screen in Drosophila S2R…”

mentioning

confidence: 99%

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Wen

Klionsky

2017

Autophagy

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“…Notably, BRD4 is also overexpressed in NSCLC, and correlates with poor prognosis in NSCLC patients (88). BET targeting has been shown to be effective in acute myeloid leukemia and multiple myeloma (89). A novel BET inhibitor, OTX015 exhibits in vitro anti-tumor activity against NSCLC cell lines harboring different oncogenic mutations (90).…”

Section: Histone Modification and Chromatin Organizationmentioning

confidence: 99%

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

et al. 2017

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The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naïve and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.

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Beating the odds: BETs in disease

Cited by 135 publications

References 116 publications

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

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