Biology subjects

Verschueren, E.

Publications and source records attributed to Verschueren, E..

5 recordsLinked to original sources

bioRxiv2018

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NF{kappa};B activating protein (NKAP) and limits NF{kappa}B activation to suppress expression of PDHK1, a NF{kappa}B target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.\n\nSIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

cancer biology↗

bioRxiv2018

Semantic context enhances neural envelope tracking

ObjectivesRecently an objective measure of speech intelligibility, based on brain responses derived from the electroencephalogram (EEG), has been developed using isolated Matrix sentences as a stimulus. We investigated whether this objective measure of speech intelligibility can also be used with natural speech as a stimulus, as this would be beneficial for clinical applications. DesignWe recorded the EEG in 19 normal-hearing participants while they listened to two types of stimuli: Matrix sentences and a natural story. Each stimulus was presented at different levels of speech intelligibility by adding speech weighted noise. Speech intelligibility was assessed in two ways for both stimuli: (1) behaviorally and (2) objectively by reconstructing the speech envelope from the EEG using a linear decoder and correlating it with the acoustic envelope. We also calculated temporal response functions (TRFs) to investigate the temporal characteristics of the brain responses in the EEG channels covering different brain areas. ResultsFor both stimulus types the correlation between the speech envelope and the reconstructed envelope increased with increasing speech intelligibility. In addition, correlations were higher for the natural story than for the Matrix sentences. Similar to the linear decoder analysis, TRF amplitudes increased with increasing speech intelligibility for both stimuli. Remarkable is that although speech intelligibility remained unchanged in the no noise and +2.5 dB SNR condition, neural speech processing was affected by the addition of this small amount of noise: TRF amplitudes across the entire scalp decreased between 0 to 150 ms, while amplitudes between 150 to 200 ms increased in the presence of noise. TRF latency changes in function of speech intelligibility appeared to be stimulus specific: The latency of the prominent negative peak in the early responses (50-300 ms) increased with increasing speech intelligibility for the Matrix sentences, but remained unchanged for the natural story. ConclusionsThese results show (1) the feasibility of natural speech as a stimulus for the objective measure of speech intelligibility, (2) that neural tracking of speech is enhanced using a natural story compared to Matrix sentences and (3) that noise and the stimulus type can change the temporal characteristics of the brain responses. These results might reflect the integration of incoming acoustic features and top-down information, suggesting that the choice of the stimulus has to be considered based on the intended purpose of the measurement.

neuroscience↗

bioRxiv2018

Neural tracking of the speech envelope in cochlear implant users

ObjectiveWhen listening to speech, the brain tracks the speech envelope. It is possible to reconstruct this envelope from EEG recordings. However, in people who hear using a cochlear implant (CI), the artifacts caused by electrical stimulation of the auditory nerve contaminate the EEG. This causes the decoder to produce an artifact-dominated reconstruction, which does not reflect the neural signal processing. The objective of this study is to develop and validate a method for assessing the neural tracking of speech envelope in CI users.\n\nApproachTo obtain EEG recordings free of stimulus artifacts, the electrical stimulation is periodically in-terrupted. During these stimulation gaps, artifact-free EEG can be sampled and used to train a linear envelope decoder. Different recording conditions were used to characterize the artifacts and their influence on the envelope reconstruction.\n\nMain resultsThe present study demonstrates for the first time that neural tracking of the speech envelope can be measured in response to ongoing electrical stimulation. The responses were validated to be truly neural and not affected by stimulus artifact.\n\nSignificanceBesides applications in audiology and neuroscience, the characterization and elimination of stimulus artifacts will enable future EEG studies involving continuous speech in CI users. Measures of neural tracking of the speech envelope reflect interesting properties of the listeners perception of speech, such as speech intelligibility or attentional state. Successful decoding of neural envelope tracking will open new possibilities to investigate the neural mechanisms of speech perception with a CI.

neuroscience↗

bioRxiv2018

Proteomic Analysis of NRROS Interactome Reveals the Presence of Chaperones and Mediators of the ERAD Pathway

Negative regulator of reactive oxygen species (NRROS, previously called LRRC33) is a leucine-rich repeat (LRR) domain containing, ER-resident transmembrane protein expressed primarily in lymphoid organs, especially in myeloid cells. We have previously demonstrated that NRROS regulates reactive oxygen species production by phagocytic cells by mediating degradation of NOX2 (gp91phox), a component of NOX2 complex responsible for the oxidative burst in these cells. Since LRR is the only functional domain in NRROS, it is likely to interact with other proteins for its biological functions. Here, by performing immunoprecipitation of NRROS and mass spectrometric analysis, we describe the NRROS interactome in macrophages and demonstrate that NRROS interacts with molecular chaperones/co-chaperones and mediators of the endoplasmic reticulum associated degradation (ERAD) pathway such as calnexin, suggesting a broader role for NRROS in protein biosynthesis and the ER quality control machinery.

biochemistry↗

bioRxiv2017

BRG1/BRM-associated factor complex subunit diversity promotes temporally distinct gene expression programs in cardiogenesis

Chromatin remodeling complexes instruct cellular differentiation and lineage specific transcription. The BRG1/BRM associated factor (BAF) complexes are important for several aspects of differentiation. We show that the catalytic subunit Brg1 has a specific role in cardiac precursors (CPs) to initiate cardiac gene expression programs and repress non-cardiac expression. Using immunoprecipitation with mass spectrometry (IP-MS), we determined the dynamic composition of BAF complexes during mammalian cardiac differentiation, and identified BAF60c (SMARCD3) and BAF170 (SMARCC2) as subunits enriched in CPs and cardiomyocytes (CM). Baf60c and Baf170 co-regulate gene expression with Brg1 in CPs, but in CMs control different gene expression programs, although still promoting a cardiac-specific gene set. BRG1, BAF60, and BAF170 all modulate chromatin accessibility, to either promote accessibility at activated genes, while closing up chromatin at repressed genes. BAF60c and BAF170 are required for proper BAF complex composition and stoichiometry, and promote BRG1 occupancy in CM. Additionally, BAF170 facilitates expulsion of BRG1-containing complexes in the transition from CP to CM. Thus, dynamic interdependent BAF complex subunit assembly modulates chromatin states and thereby directs temporal gene expression programs in cardiogenesis.\n\nSignificance statementBRG1/BRM associated factors (BAF) form multi-subunit protein complexes that reorganize chromatin and regulate transcription. Specific BAF complex subunits have important roles during cell differentiation and development. We systematically identify BAF subunit composition and find temporal enrichment of subunits during cardiomyocyte differentiation. We find the catalytic subunit BRG1 has important contributions in initiating gene expression programs in cardiac progenitors along with cardiac-enriched subunits BAF60c and BAF170. Both these proteins regulated BAF subunit composition and chromatin accessibility and prevent expression of non-cardiac developmental genes during precursor to cardiomyocyte differentiation. Mechanistically, we find BAF170 destabilizes the BRG1 complex and expels BRG1 from cardiomyocyte-specific genes. Thus, our data shows synergies between diverse BAF subunits in facilitating temporal gene expression programs during cardiogenesis.

developmental biology↗