Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR

The role of TET-mediated DNA hydroxymethylation in prostate cancer

Massie C. is funded by an ERC grant (337905) and acknowledges support of the University of Cambridge, the Cancer Research UK Cambridge Centre and Hutchison Whampoa Limited. Claessens F. and Joniau S. hold grants from Fonds Wetenschappelijk Onderzoek-Vlaanderen (GOA9816N, G.0684.12N, G.0830.13N). Van den Broeck T. is supported by a PhD fellowship from Fonds Wetenschappelijk Onderzoek-Vlaanderen (11ZO616N). This work was also supported by the KU Leuven (GOA/15/017) and Kom op tegen Kanker.Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.PostprintPeer reviewe

Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G>A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR

Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR

Unravelling the molecular interactions between α7 nicotinic receptor and a ric3 variant associated with backward speech

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR

Multidisciplinary investigation links backward-speech trait and working memory through genetic mutation

Case studies of unusual traits can provide unique snapshots of the effects of modified systems. In this study, we report on an individual from a Serbian family with the ability to rapidly, accurately and voluntarily speak backwards. We consider psychological, neural and genetic correlates of this trait to identify specific relevant neural mechanisms and new molecular pathways for working memory and speech-related tasks. EEG data suggest that the effect of word reversal precedes semantic integration of visually presented backward-words, and that event-related potentials above the frontal lobe are affected by both word reversal and the maintenance of backward-words in working memory. fMRI revealed that the left fusiform gyrus may facilitate the production of backward-speech. Exome sequencing identified three novel coding variants of potential significance in the RIC3, RIPK1 and ZBED5 genes. Taken together, our data suggest that, in this individual, the ability to speak backwards is afforded by an extraordinary working memory capacity. We hypothesise that this is served by cholinergic projections from the basal forebrain to the frontal cortex and supported by visual semantic loops within the left fusiform gyrus and that these neural processes may be mediated by a genetic mutation in RIC3; a chaperone for nicotinic acetylcholine receptors

A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation

Estrogen receptor α (ERα) is an enhancer activating transcription factor, a key driver of breast cancer and a main target for cancer therapy. ERα-mediated gene regulation requires proper chromatin-conformation to facilitate interactions between ERα-bound enhancers and their target promoters. A major determinant of chromatin structure is the CCCTC-binding factor (CTCF), that dimerizes and together with cohesin stabilizes chromatin loops and forms the boundaries of topologically associated domains. However, whether CTCF-binding elements (CBEs) are essential for ERα-driven cell proliferation is unknown. To address this question in a global manner, we implemented a CRISPR-based functional genetic screen targeting CBEs located in the vicinity of ERα-bound enhancers. We identified four functional CBEs and demonstrated the role of one of them in inducing chromatin conformation changes in favor of activation of PREX1, a key ERα target gene in breast cancer. Indeed, high PREX1 expression is a bona-fide marker of ERα-dependency in cell lines, and is associated with good outcome after anti-hormonal treatment. Altogether, our data show that distinct CTCF-mediated chromatin structures are required for ERα- driven breast cancer cell proliferation

Enzalutamide therapy for advanced prostate cancer:efficacy, resistance and beyond

\u3cp\u3eThe androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.\u3c/p\u3

Treatment-induced changes in the androgen receptor axis: Liquid biopsies as diagnostic/prognostic tools for prostate cancer.

Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer

Molecular underpinnings of enzalutamide resistance

Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure. This review will focus on the molecular underpinnings of enzalutamide resistance, bridging the gap between the preclinical and clinical research on novel therapeutic strategies for combating this lethal stage of prostate cancer.status: publishe