Biology subjects

Wouters, M.

Publications and source records attributed to Wouters, M..

5 recordsLinked to original sources

bioRxiv2026

ULTRAPETALA1 remodels PRC2 recruitment to nucleosomes

Polycomb Repressive Complex 2 (PRC2) establishes transcriptional repression through trimethylation of histone H3 lysine 27 (H3K27me3), a modification essential for developmental patterning. Here, we describe a novel plant-specific PRC2 variant (PRC2.3) that employs a distinct nucleosome-targeting mechanism mediated by accessory factor ULTRAPETALA1 (ULT1), which promotes H3K27me3 deposition at over 1,300 developmental genes. The cryo-EM structure of the PRC2SWN-ULT1-nucleosome complex reveals that ULT1 antagonizes the canonical PRC2 binding mode and instead bridges PRC2 to the nucleosome using its own interaction surfaces. ULT1 binds consecutive purines in the nucleosomal DNA and the histone H2A/H2B acidic patch, while enabling PRC2 to accommodate H3K36 modifications. We further show that in planta ULT1 enhances H3K27me3 at purine-rich loci and at genes associated with H3K36 marks, and identify the ULT1-H2A/H2B interface as required for reproductive transition and flower organogenesis. Our findings demonstrate that PRC2 can deploy mechanistically distinct recruitment strategies to control key developmental switches.

Molecular Biology↗

bioRxiv2026

Peripheral phoneme encoding and discrimination in aging and hearing impairment

HighlightsO_LISpeech EEG shows age- and OHC-related vulnerability of high-CF envelope coding. C_LIO_LISpeech EEG shows low-CF envelope encoding stays intact with age. C_LIO_LIFine-structure contrast discrimination worsens with OHC loss in quiet. C_LIO_LIFine-structure contrast discrimination worsens with age in contralateral noise. C_LIO_LIPhoneme discrimination involving high-frequency contrasts remains robust with age. C_LIO_LIPeripheral coding strength is not directly reflected at behavioral level. C_LI Speech perception difficulties in noise are common among older adults and individuals with hearing impairment, but also occur among younger adults whose audiometric thresholds are within the clinically-normal range. We examined how aging, cochlear synaptopathy (CS), and outer hair cell (OHC) damage affect speech encoding and phoneme discrimination. Envelope-following responses (EFRs) to rectangular amplitude-modulated (RAM) tones and speech-like phoneme pairs were recorded in quiet using EEG, and behavioral discrimination was assessed in quiet, and with ipsilateral and contralateral noise. Stimuli were designed to target temporal envelope (TENV) or temporal fine structure (TFS) encoding. Results showed that RAM-EFR amplitudes decreased gradually with increasing age, consistent with emerging CS, while magnitudes of high-frequency TENV-based EFRs in quiet were most reduced in older hearing-impaired subjects with combined CS and OHC damage. In contrast, EFRs targeting low-frequency TENV encoding in quiet remained preserved. Behaviorally, discrimination of predominantly TFS-based phoneme contrasts worsened with OHC loss and age in quiet and contralateral noise, respectively, whereas discrimination of predominantly TENV-based contrasts showed no significant age effect. Considering that high-frequency contrasts are discriminated via place-based spectral cues, low-frequency contrasts rely on TFS, and the EFR reflects primarily TENV, this framework explains why EFRs decline for high-frequency cues without perceptual loss, while EFRs remain stable for low-frequency cues even as TFS-based discrimination deteriorates. These findings highlight the need to investigate how neural coding deficits relate to perception. Combining electrophysiological and behavioral measures might provide a framework for detecting subclinical auditory deficits to earlier diagnose age-related and hidden hearing loss.

neuroscience↗

bioRxiv2023

Neural adaptation at stimulus onset and speed of neural processing as critical contributors to speech comprehension independent of hearing threshold or age

Loss of afferent auditory fiber function (cochlear synaptopathy) has been suggested to occur before a clinically measurable deterioration of subjective hearing threshold. This so-called "hidden" hearing loss is characterized by speech comprehension difficulties. We examined young, middle-aged, and older individuals with and without hearing loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (DPOAE), auditory brainstem responses (ABR), auditory steady state responses (ASSR), speech comprehension (OLSA), and syllable discrimination in quiet and noise. After normalizing OLSA thresholds for PT thresholds ("PNOT"), differences in speech comprehension still remained and showed no significant dependence on age, allowing us to categorize participants into groups with good, standard, and poor speech comprehension. Listeners with poor speech comprehension in quiet exhibited smaller firing rate adaptions at stimulus onset (as measured by the difference between DPOAE threshold and pure-tone threshold) and delayed supra-threshold ABR waves I-V, suggesting high spontaneous rate low threshold fiber cochlear synaptopathy. In contrast, when speech comprehension was tested in noise, listeners with poor speech comprehension had larger DPOAEs acceptance rate, putatively resulting from altered basilar membrane compression (recruitment). This was linked with higher uncomfortable loudness levels and larger ASSR amplitudes. Moreover, performance in phoneme discrimination was significantly different below (/o/-/u/) and above the phase-locking limit (/i/-/y/), depending on whether vowels were presented in quiet or ipsilateral noise. This suggests that neural firing rate adaptation at stimulus onset is critical for speech comprehension, independent of hearing threshold and age, whereas the recruitment phenomenon counterbalances the loss in speech-in-noise discrimination due to impaired threshold. Significance StatementAge-related hearing loss is the third largest modifiable risk factor for cognitive decline. It has been suggested that the link between hearing loss and cognitive decline is not fully explained by hearing threshold loss. We here suggest that language comprehension deficits may be used as an early indication of future hearing loss and therefore cognitive decline. We found that, independent of age and pure-tone thresholds, speech comprehension in quiet and ipsilateral noise depend on different onset firing-rate adaptations of inner hair cells (measured by DPOAE threshold), along with cochlear synaptopathy of high spontaneous rate auditory nerve fibers and neural spiking synchronicity. These measures may be used as possible future indicators of risk for cognitive decline.

neuroscience↗

bioRxiv2023

Aberrant N-glycosylation in pathogenic variants of adenosine deaminase 2 underlying human ADA2 deficiency

Human deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by pathogenic variants in ADA2 that lead to impaired deaminase activity. Recently, a lysosomal function of ADA2 has been proposed but an intracellular form of the protein has not yet been characterized. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify an intracellular low-molecular-weight (LMW) form of ADA2 that undergoes glycan trimming by -mannosidases and is absent in DADA2 macrophages. Subcellular fractionation and immunofluorescence microscopy demonstrate that LMW-ADA2 is localized in the lysosomes. By overexpression of 34 ADA2 variants in HEK293T and U-937 cells, we show that absence of LMW-ADA2 strongly correlates with reduced deaminase activity and predicts variant pathogenicity. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2. Thereby, we introduce a protein correlate of the recently described lysosomal form of ADA2. SummaryEhlers et al. demonstrate that mutant ADA2 fails to undergo glycan processing beyond the ER leading to the absence of intracellular low-molecular-weight (LMW) ADA2 in DADA2 patients macrophages. LMW-ADA2 localizes to the lysosomes and can be generated from extracellular wild-type ADA2.

immunology↗

bioRxiv2019

H3K4me3 is neither instructive for, nor informed by, transcription.

H3K4me3 is a near-universal histone modification found predominantly at the 5 region of genes, with a well-documented association with gene activity. H3K4me3 has been ascribed roles as both an instructor of gene expression and also a downstream consequence of expression, yet neither has been convincingly proven on a genome-wide scale. Here we test these relationships using a combination of bioinformatics, modelling and experimental data from budding yeast in which the levels of H3K4me3 have been massively ablated. We find that loss of H3K4me3 has no effect on the levels of nascent transcription or transcript in the population. Moreover, we observe no change in the rates of transcription initiation, elongation, mRNA export or turnover, or in protein levels, or cell-to-cell variation of mRNA. Loss of H3K4me3 also has no effect on the large changes in gene expression patterns that follow galactose induction. Conversely, loss of RNA polymerase from the nucleus has no effect on the pattern of H3K4me3 deposition and little effect on its levels, despite much larger changes to other chromatin features. Furthermore, large genome-wide changes in transcription, both in response to environmental stress and during metabolic cycling, are not accompanied by corresponding changes in H3K4me3. Thus, despite the correlation between H3K4me3 and gene activity, neither appear to be necessary to maintain levels of the other, nor to influence their changes in response to environmental stimuli. When we compare gene classes with very different levels of H3K4me3 but highly similar transcription levels we find that H3K4me3-marked genes are those whose expression is unresponsive to environmental changes, and that their histones are less acetylated and dynamically turned-over. Constitutive genes are generally well-expressed, which may alone explain the correlation between H3K4me3 and gene expression, while the biological role of H3K4me3 may have more to do with this distinction in gene class.

genomics↗