Publications by authors named "Samuel Demharter"

15 Publications

  • Page 1 of 1

Coordinated maintenance of H3K36/K27 methylation by histone demethylases preserves germ cell identity and immortality.

Cell Rep 2021 Nov;37(8):110050

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes vej 5, Copenhagen DK-2200, Denmark. Electronic address:

Germ cells have evolved unique mechanisms to ensure the transmission of genetically and nongenetically encoded information, whose alteration compromises germ cell immortality. Chromatin factors play fundamental roles in these mechanisms. H3K36 and H3K27 methyltransferases shape and propagate a pattern of histone methylation essential for C. elegans germ cell maintenance, but the role of respective histone demethylases remains unexplored. Here, we show that jmjd-5 regulates H3K36me2 and H3K27me3 levels, preserves germline immortality, and protects germ cell identity by controlling gene expression. The transcriptional and biological effects of jmjd-5 loss can be hindered by the removal of H3K27demethylases, indicating that H3K36/K27 demethylases act in a transcriptional framework and promote the balance between H3K36 and H3K27 methylation required for germ cell immortality. Furthermore, we find that in wild-type, but not in jmjd-5 mutants, alterations of H3K36 methylation and transcription occur at high temperature, suggesting a role for jmjd-5 in adaptation to environmental changes.
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http://dx.doi.org/10.1016/j.celrep.2021.110050DOI Listing
November 2021

A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder.

Neuropsychopharmacology 2021 06 8;46(7):1324-1332. Epub 2021 Apr 8.

The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.
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http://dx.doi.org/10.1038/s41386-021-01002-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134553PMC
June 2021

Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 Nov 19;11(1):5988. Epub 2020 Nov 19.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.
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http://dx.doi.org/10.1038/s41467-020-19869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678822PMC
November 2020

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 10 7;11(1):5038. Epub 2020 Oct 7.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.
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http://dx.doi.org/10.1038/s41467-020-18752-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541486PMC
October 2020

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

EMBO J 2020 09 3;39(18):e105759. Epub 2020 Aug 3.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Parvalbumin-positive (PV ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2 PV interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.
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http://dx.doi.org/10.15252/embj.2020105759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507454PMC
September 2020

Joint analysis of heterogeneous single-cell RNA-seq dataset collections.

Nat Methods 2019 08 15;16(8):695-698. Epub 2019 Jul 15.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Single-cell RNA sequencing is often applied in study designs that include multiple individuals, conditions or tissues. To identify recurrent cell subpopulations in such heterogeneous collections, we developed Conos, an approach that relies on multiple plausible inter-sample mappings to construct a global graph connecting all measured cells. The graph enables identification of recurrent cell clusters and propagation of information between datasets in multi-sample or atlas-scale collections.
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http://dx.doi.org/10.1038/s41592-019-0466-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684315PMC
August 2019

Tracing the origin of adult intestinal stem cells.

Nature 2019 06 15;570(7759):107-111. Epub 2019 May 15.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Adult intestinal stem cells are located at the bottom of crypts of Lieberkühn, where they express markers such as LGR5 and fuel the constant replenishment of the intestinal epithelium. Although fetal LGR5-expressing cells can give rise to adult intestinal stem cells, it remains unclear whether this population in the patterned epithelium represents unique intestinal stem-cell precursors. Here we show, using unbiased quantitative lineage-tracing approaches, biophysical modelling and intestinal transplantation, that all cells of the mouse intestinal epithelium-irrespective of their location and pattern of LGR5 expression in the fetal gut tube-contribute actively to the adult intestinal stem cell pool. Using 3D imaging, we find that during fetal development the villus undergoes gross remodelling and fission. This brings epithelial cells from the non-proliferative villus into the proliferative intervillus region, which enables them to contribute to the adult stem-cell niche. Our results demonstrate that large-scale remodelling of the intestinal wall and cell-fate specification are closely linked. Moreover, these findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissues following damage, revealing that stem-cell identity is an induced rather than a hardwired property.
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http://dx.doi.org/10.1038/s41586-019-1212-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986928PMC
June 2019

HLA-DM Stabilizes the Empty MHCII Binding Groove: A Model Using Customized Natural Move Monte Carlo.

J Chem Inf Model 2019 06 28;59(6):2894-2899. Epub 2019 May 28.

Department of Computer Science , University of Oxford , Oxford OX1 3QD , United Kingdom.

MHC class II molecules bind peptides derived from extracellular proteins that have been ingested by antigen-presenting cells and display them to the immune system. Peptide loading occurs within the antigen-presenting cell and is facilitated by HLA-DM. HLA-DM stabilizes the open conformation of the MHCII binding groove when no peptide is bound. While a structure of the MHCII/HLA-DM complex exists, the mechanism of stabilization is still largely unknown. Here, we applied customized Natural Move Monte Carlo to investigate this interaction. We found a possible long-range mechanism that implicates the configuration of the membrane-proximal globular domains in stabilizing the open state of the empty MHCII binding groove.
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http://dx.doi.org/10.1021/acs.jcim.9b00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007188PMC
June 2019

Neuroserpin expression during human brain development and in adult brain revealed by immunohistochemistry and single cell RNA sequencing.

J Anat 2019 09 15;235(3):543-554. Epub 2019 Jan 15.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Neuroserpin is a serine-protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia-ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is still no information in the literature on its distribution during human brain development. The present study provides a detailed description of the changing spatiotemporal patterns of neuroserpin focusing on physiological human brain development. Five stages were distinguished within our examined age range which spanned from the 7th gestational week until adulthood. In particular, subplate and deep cortical plate neurons were identified as the main sources of neuroserpin production between the 25th gestational week and the first postnatal month. Our immunohistochemical findings were substantiated by single cell RNA sequencing data showing specific neuronal and glial cell types expressing neuroserpin. The characterization of neuroserpin expression during physiological human brain development is essential for forthcoming studies which will explore its involvement in pathological conditions, such as perinatal hypoxia-ischaemia and adult stroke in human.
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http://dx.doi.org/10.1111/joa.12931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704272PMC
September 2019

In silico structural modeling of multiple epigenetic marks on DNA.

Bioinformatics 2018 01;34(1):41-48

Department of Computer Science, Oxford University, OX1?3QD Oxford, UK.

Availability And Implementation: The code together with examples and tutorials are available from http://www.cs.ox.ac.uk/mosaics.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btx516DOI Listing
January 2018

Modeling Functional Motions of Biological Systems by Customized Natural Moves.

Biophys J 2016 Aug;111(4):710-721

Department of Computer Science, University of Oxford, Oxford, UK. Electronic address:

Simulating the functional motions of biomolecular systems requires large computational resources. We introduce a computationally inexpensive protocol for the systematic testing of hypotheses regarding the dynamic behavior of proteins and nucleic acids. The protocol is based on natural move Monte Carlo, a highly efficient conformational sampling method with built-in customization capabilities that allows researchers to design and perform a large number of simulations to investigate functional motions in biological systems. We demonstrate the use of this protocol on both a protein and a DNA case study. Firstly, we investigate the plasticity of a class II major histocompatibility complex in the absence of a bound peptide. Secondly, we study the effects of the epigenetic mark 5-hydroxymethyl on cytosine on the structure of the Dickerson-Drew dodecamer. We show how our customized natural moves protocol can be used to investigate causal relationships of functional motions in biological systems.
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http://dx.doi.org/10.1016/j.bpj.2016.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002067PMC
August 2016

Exploring peptide/MHC detachment processes using hierarchical natural move Monte Carlo.

Bioinformatics 2016 Jan 22;32(2):181-6. Epub 2015 Sep 22.

Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK.

Motivation: The binding between a peptide and a major histocompatibility complex (MHC) is one of the most important processes for the induction of an adaptive immune response. Many algorithms have been developed to predict peptide/MHC (pMHC) binding. However, no approach has yet been able to give structural insight into how peptides detach from the MHC.

Results: In this study, we used a combination of coarse graining, hierarchical natural move Monte Carlo and stochastic conformational optimization to explore the detachment processes of 32 different peptides from HLA-A*02:01. We performed 100 independent repeats of each stochastic simulation and found that the presence of experimentally known anchor amino acids affects the detachment trajectories of our peptides. Comparison with experimental binding affinity data indicates the reliability of our approach (area under the receiver operating characteristic curve 0.85). We also compared to a 1000 ns molecular dynamics simulation of a non-binding peptide (AAAKTPVIV) and HLA-A*02:01. Even in this simulation, the longest published for pMHC, the peptide does not fully detach. Our approach is orders of magnitude faster and as such allows us to explore pMHC detachment processes in a way not possible with all-atom molecular dynamics simulations.

Availability And Implementation: The source code is freely available for download at http://www.cs.ox.ac.uk/mosaics/.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708099PMC
January 2016

Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands.

Cell 2015 Mar 26;160(6):1196-208. Epub 2015 Feb 26.

Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA. Electronic address:

Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems.
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http://dx.doi.org/10.1016/j.cell.2015.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766813PMC
March 2015

Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations.

Brief Bioinform 2015 Nov 28;16(6):1035-44. Epub 2015 Feb 28.

The interaction between T-cell receptors (TCRs) and major histocompatibility complex (MHC)-bound epitopes is one of the most important processes in the adaptive human immune response. Several hypotheses on TCR triggering have been proposed. Many of them involve structural and dynamical adjustments in the TCR/peptide/MHC interface. Molecular Dynamics (MD) simulations are a computational technique that is used to investigate structural dynamics at atomic resolution. Such simulations are used to improve understanding of signalling on a structural level. Here we review how MD simulations of the TCR/peptide/MHC complex have given insight into immune system reactions not achievable with current experimental methods. Firstly, we summarize methods of TCR/peptide/MHC complex modelling and TCR/peptide/MHC MD trajectory analysis methods. Then we classify recently published simulations into categories and give an overview of approaches and results. We show that current studies do not come to the same conclusions about TCR/peptide/MHC interactions. This discrepancy might be caused by too small sample sizes or intrinsic differences between each interaction process. As computational power increases future studies will be able to and should have larger sample sizes, longer runtimes and additional parts of the immunological synapse included.
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http://dx.doi.org/10.1093/bib/bbv005DOI Listing
November 2015
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