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  1. Artikel ; Online: Middle-Down MS is Ready to Answer Complex Questions in Chromatin Biology.

    Sidoli, Simone

    Proteomics

    2018  Band 18, Heft 13, Seite(n) e1800131

    Abstract: Histones are the most abundant protein family in the cells of complex organisms such as mammals and, together with DNA, they define the backbone of chromatin. Histone PTMs are key players of chromatin biology, as they function as anchors for proteins ... ...

    Abstract Histones are the most abundant protein family in the cells of complex organisms such as mammals and, together with DNA, they define the backbone of chromatin. Histone PTMs are key players of chromatin biology, as they function as anchors for proteins that bind and modulate chromatin readout, including gene expression. Middle-down mass spectrometry (MS) has been optimized for about 10 years to study histone N-terminal tails, but it has been rarely applied to identify the role of coexisting histone marks in biology. In this work, Jiang et al. used middle-down MS to study the dynamics of coexisting PTMs on histone H4 in two breast cancer cell lines. They found that overall serine 1 phosphorylation (S1ph) is mildly regulated during the cell cycle, but S1ph coexistence frequency with acetylations and methylations on the lysine residues of the N-terminal tail is remarkably tuned during S phase and G2/M phase. Together, the team placed another benchmark proving that MS analysis of combinatorial histone PTMs provides a more comprehensive view on chromatin state than studying individual marks. We should then constantly question ourselves regarding the limitations of analyzing single PTMs when we attempt to define their effect on protein functions.
    Mesh-Begriff(e) Animals ; Chromatin ; Histone Code ; Histones/genetics ; Mass Spectrometry ; Protein Processing, Post-Translational
    Chemische Substanzen Chromatin ; Histones
    Sprache Englisch
    Erscheinungsdatum 2018-06-07
    Erscheinungsland Germany
    Dokumenttyp Journal Article ; Comment
    ZDB-ID 2032093-0
    ISSN 1615-9861 ; 1615-9853
    ISSN (online) 1615-9861
    ISSN 1615-9853
    DOI 10.1002/pmic.201800131
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  2. Artikel ; Online: Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells.

    Flores, Julio C / Sidoli, Simone / Dawlaty, Meelad M

    iScience

    2023  Band 26, Heft 7, Seite(n) 107170

    Abstract: Tet2 is a member of the Ten-eleven translocation (Tet1/2/3) family of enzymes and is expressed in embryonic stem cells (ESCs). It demethylates DNA (catalytic functions) and partners with chromatin modifiers (noncatalytic functions) to regulate genes. ... ...

    Abstract Tet2 is a member of the Ten-eleven translocation (Tet1/2/3) family of enzymes and is expressed in embryonic stem cells (ESCs). It demethylates DNA (catalytic functions) and partners with chromatin modifiers (noncatalytic functions) to regulate genes. However, the significance of these functions in ESCs is less defined. Using Tet2 catalytic mutant (
    Sprache Englisch
    Erscheinungsdatum 2023-06-17
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.107170
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  3. Artikel: Ten questions to AI regarding the present and future of proteomics.

    Stransky, Stephanie / Sun, Yan / Shi, Xuyan / Sidoli, Simone

    Frontiers in molecular biosciences

    2023  Band 10, Seite(n) 1295721

    Abstract: The role of a scientist is at first not so different from a philosopher. They both need to question common thinking and evaluate whether reality is not as we always thought. Based on this, we need to design hypotheses, experiments, and analyses to prove ... ...

    Abstract The role of a scientist is at first not so different from a philosopher. They both need to question common thinking and evaluate whether reality is not as we always thought. Based on this, we need to design hypotheses, experiments, and analyses to prove our alternative vision. Artificial Intelligence (AI) is rapidly moving from an "assistant" into a proper "colleague" for literature mining, data analysis and interpretation, and literally having (almost) real scientific conversations. However, being AI based on existing information, if we rely on it excessively will we still be able to question the
    Sprache Englisch
    Erscheinungsdatum 2023-11-23
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2023.1295721
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  4. Artikel ; Online: Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5.

    Yheskel, Matanel / Sidoli, Simone / Secombe, Julie

    Epigenetics & chromatin

    2023  Band 16, Heft 1, Seite(n) 8

    Abstract: Background: KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to ... ...

    Abstract Background: KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to demethylase-independent gene regulatory functions that remain less characterized. To expand our understanding of the mechanisms that contribute to KDM5-mediated transcription regulation, we used TurboID proximity labeling to identify KDM5-interacting proteins.
    Results: Using Drosophila melanogaster, we enriched for biotinylated proteins from KDM5-TurboID-expressing adult heads using a newly generated control for DNA-adjacent background in the form of dCas9:TurboID. Mass spectrometry analyses of biotinylated proteins identified both known and novel candidate KDM5 interactors, including members of the SWI/SNF and NURF chromatin remodeling complexes, the NSL complex, Mediator, and several insulator proteins.
    Conclusions: Combined, our data shed new light on potential demethylase-independent activities of KDM5. In the context of KDM5 dysregulation, these interactions may play key roles in the alteration of evolutionarily conserved transcriptional programs implicated in human disorders.
    Mesh-Begriff(e) Animals ; Cell Nucleus/metabolism ; Drosophila melanogaster/genetics ; Drosophila Proteins/metabolism ; Gene Expression Regulation ; Histone Demethylases/metabolism
    Chemische Substanzen Drosophila Proteins ; Histone Demethylases (EC 1.14.11.-) ; Lid protein, Drosophila (EC 1.14.11.-)
    Sprache Englisch
    Erscheinungsdatum 2023-02-18
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2462129-8
    ISSN 1756-8935 ; 1756-8935
    ISSN (online) 1756-8935
    ISSN 1756-8935
    DOI 10.1186/s13072-023-00481-y
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  5. Artikel ; Online: The role of histone H3 lysine demethylases in glioblastoma.

    Young, Dejauwne / Guha, Chandan / Sidoli, Simone

    Cancer metastasis reviews

    2023  Band 42, Heft 2, Seite(n) 445–454

    Abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with an average survival of 15-18 months. Part of its malignancy derives from epigenetic regulation that occurs as the tumor develops and after therapeutic treatment. Specifically, ... ...

    Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with an average survival of 15-18 months. Part of its malignancy derives from epigenetic regulation that occurs as the tumor develops and after therapeutic treatment. Specifically, enzymes involved in removing methylations from histone proteins on chromatin, i.e., lysine demethylases (KDMs), have a significant impact on GBM biology and reoccurrence. This knowledge has paved the way to considering KDMs as potential targets for GBM treatment. For example, increases in trimethylation of histone H3 on the lysine 9 residue (H3K9me3) via inhibition of KDM4C and KDM7A has been shown to lead to cell death in Glioblastoma initiating cells. KDM6 has been shown to drive Glioma resistance to receptor tyrosine kinase inhibitors and its inhibition decreases tumor resistance. In addition, increased expression of the histone methyltransferase MLL4 and UTX histone demethylase are associated with prolonged survival in a subset of GBM patients, potentially by regulating histone methylation on the promoter of the mgmt gene. Thus, the complexity of how histone modifiers contribute to glioblastoma pathology and disease progression is yet to be fully understood. To date, most of the current work on histone modifying enzymes in GBM are centered upon histone H3 demethylase enzymes. In this mini-review, we summarize the current knowledge on the role of histone H3 demethylase enzymes in Glioblastoma tumor biology and therapy resistance. The objective of this work is to highlight the current and future potential areas of research for GBM epigenetics therapy.
    Mesh-Begriff(e) Humans ; Histones/genetics ; Histones/metabolism ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Glioblastoma/genetics ; Glioblastoma/pathology ; Lysine/genetics ; Lysine/metabolism ; Epigenesis, Genetic ; Jumonji Domain-Containing Histone Demethylases/genetics ; Jumonji Domain-Containing Histone Demethylases/metabolism
    Chemische Substanzen Histones ; Histone Demethylases (EC 1.14.11.-) ; Lysine (K3Z4F929H6) ; KDM4C protein, human ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM7A protein, human (EC 1.14.11.-)
    Sprache Englisch
    Erscheinungsdatum 2023-06-08
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604857-2
    ISSN 1573-7233 ; 0167-7659
    ISSN (online) 1573-7233
    ISSN 0167-7659
    DOI 10.1007/s10555-023-10114-1
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  6. Artikel ; Online: Characterization of the intracellular neurexin interactome by in vivo proximity ligation suggests its involvement in presynaptic actin assembly.

    Schaan Profes, Marcos / Tiroumalechetty, Araven / Patel, Neel / Lauar, Stephanie S / Sidoli, Simone / Kurshan, Peri T

    PLoS biology

    2024  Band 22, Heft 1, Seite(n) e3002466

    Abstract: Neurexins are highly spliced transmembrane cell adhesion molecules that bind an array of partners via their extracellular domains. However, much less is known about the signaling pathways downstream of neurexin's largely invariant intracellular domain ( ... ...

    Abstract Neurexins are highly spliced transmembrane cell adhesion molecules that bind an array of partners via their extracellular domains. However, much less is known about the signaling pathways downstream of neurexin's largely invariant intracellular domain (ICD). Caenorhabditis elegans contains a single neurexin gene that we have previously shown is required for presynaptic assembly and stabilization. To gain insight into the signaling pathways mediating neurexin's presynaptic functions, we employed a proximity ligation method, endogenously tagging neurexin's intracellular domain with the promiscuous biotin ligase TurboID, allowing us to isolate adjacent biotinylated proteins by streptavidin pull-down and mass spectrometry. We compared our experimental strain to a control strain in which neurexin, endogenously tagged with TurboID, was dispersed from presynaptic active zones by the deletion of its C-terminal PDZ-binding motif. Selection of this control strain, which differs from the experimental strain only in its synaptic localization, was critical to identifying interactions specifically occurring at synapses. Using this approach, we identified both known and novel intracellular interactors of neurexin, including active zone scaffolds, actin-binding proteins (including almost every member of the Arp2/3 complex), signaling molecules, and mediators of RNA trafficking, protein synthesis and degradation, among others. Characterization of mutants for candidate neurexin interactors revealed that they recapitulate aspects of the nrx-1(-) mutant phenotype, suggesting they may be involved in neurexin signaling. Finally, to investigate a possible role for neurexin in local actin assembly, we endogenously tagged its intracellular domain with actin depolymerizing and sequestering peptides (DeActs) and found that this led to defects in active zone assembly. Together, these results suggest neurexin's intracellular domain may be involved in presynaptic actin-assembly, and furthermore highlight a novel approach to achieving high specificity for in vivo proteomics experiments.
    Mesh-Begriff(e) Animals ; Actins ; Neurexins ; Microfilament Proteins ; Actin-Related Protein 2-3 Complex ; Caenorhabditis elegans/genetics ; Cell Adhesion Molecules, Neuronal ; Caenorhabditis elegans Proteins/genetics
    Chemische Substanzen Actins ; Neurexins ; Microfilament Proteins ; Actin-Related Protein 2-3 Complex ; nrx-1 protein, C elegans ; Cell Adhesion Molecules, Neuronal ; Caenorhabditis elegans Proteins
    Sprache Englisch
    Erscheinungsdatum 2024-01-22
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.3002466
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  7. Artikel ; Online: Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens.

    Mews, Philipp / Sosnick, Lucas / Gurung, Ashik / Sidoli, Simone / Nestler, Eric J

    Science signaling

    2024  Band 17, Heft 832, Seite(n) eadl4738

    Abstract: Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The ... ...

    Abstract Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain's reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.
    Mesh-Begriff(e) Mice ; Animals ; Nucleus Accumbens/metabolism ; Proteomics ; Cocaine/pharmacology ; Cocaine-Related Disorders/genetics ; Cocaine-Related Disorders/metabolism ; Cocaine-Related Disorders/psychology ; Chromatin/metabolism
    Chemische Substanzen Cocaine (I5Y540LHVR) ; Chromatin
    Sprache Englisch
    Erscheinungsdatum 2024-04-16
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.adl4738
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  8. Artikel ; Online: Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model.

    Stransky, Stephanie / Cutler, Ronald / Aguilan, Jennifer / Nieves, Edward / Sidoli, Simone

    Epigenetics & chromatin

    2022  Band 15, Heft 1, Seite(n) 35

    Abstract: Background: Three-dimensional (3D) cell culture has emerged as an alternative approach to 2D flat culture to model more accurately the phenotype of solid tissue in laboratories. Culturing cells in 3D more precisely recapitulates physiological conditions ...

    Abstract Background: Three-dimensional (3D) cell culture has emerged as an alternative approach to 2D flat culture to model more accurately the phenotype of solid tissue in laboratories. Culturing cells in 3D more precisely recapitulates physiological conditions of tissues, as these cells reduce activities related to proliferation, focusing their energy consumption toward metabolism and homeostasis.
    Results: Here, we demonstrate that 3D liver spheroids are a suitable system to model chromatin dynamics and response to epigenetics inhibitors. To delay necrotic tissue formation despite proliferation arrest, we utilize rotating bioreactors that apply active media diffusion and low shearing forces. We demonstrate that the proteome and the metabolome of our model resemble typical liver functions. We prove that spheroids respond to sodium butyrate (NaBut) treatment, an inhibitor of histone deacetylases (HDACi), by upregulating histone acetylation and transcriptional activation. As expected, NaBut treatment impaired specific cellular functions, including the energy metabolism. More importantly, we demonstrate that spheroids reestablish their original proteome and transcriptome, including pre-treatment levels of histone acetylation, metabolism, and protein expression once the standard culture condition is restored after treatment. Given the slow replication rate (> 40 days) of cells in 3D spheroids, our model enables to monitor the recovery of approximately the same cells that underwent treatment, demonstrating that NaBut does not have long-lasting effects on histone acetylation and gene expression. These results suggest that our model system can be used to quantify molecular memory on chromatin.
    Conclusion: Together, we established an innovative cell culture system that can be used to model anomalously decondensing chromatin in physiological cell growth and rule out epigenetics inheritance if cells recover the original phenotype after treatment. The transient epigenetics effects demonstrated here highlight the relevance of using a 3D culture model system that could be very useful in studies requiring long-term drug treatment conditions that would not be possible using a 2D cell monolayer system.
    Mesh-Begriff(e) Acetylation ; Histones ; Proteome ; Liver ; Protein Processing, Post-Translational ; Chromatin
    Chemische Substanzen Histones ; Proteome ; Chromatin
    Sprache Englisch
    Erscheinungsdatum 2022-11-21
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2462129-8
    ISSN 1756-8935 ; 1756-8935
    ISSN (online) 1756-8935
    ISSN 1756-8935
    DOI 10.1186/s13072-022-00470-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel: Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis.

    Barbaro, John M / Sidoli, Simone / Cuervo, Ana Maria / Berman, Joan W

    Biomedicines

    2022  Band 10, Heft 6

    Abstract: HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) ... ...

    Abstract HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth.
    Sprache Englisch
    Erscheinungsdatum 2022-05-27
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines10061257
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  10. Artikel ; Online: Morphine disrupts macrophage functions even during HIV infection.

    Barbaro, John M / Jaureguiberry-Bravo, Matias / Sidoli, Simone / Berman, Joan W

    Journal of leukocyte biology

    2022  Band 112, Heft 5, Seite(n) 1317–1328

    Abstract: HIV-associated neurocognitive impairment (HIV-NCI) is a debilitating comorbidity that reduces quality of life in 15-40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. ... ...

    Abstract HIV-associated neurocognitive impairment (HIV-NCI) is a debilitating comorbidity that reduces quality of life in 15-40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. Monocyte-derived macrophages (MDMs) harbor HIV in the CNS even in PWH on ART. We hypothesized that morphine (MOR), a metabolite of heroin, further dysregulates functional processes in MDMs to increase neuropathogenesis. We found that, in uninfected and HIV-infected primary human MDMs, MOR activates these cells by increasing phagocytosis and up-regulating reactive oxygen species. Effects of MOR on phagocytosis were dependent on μ-opioid receptor activity and were mediated, in part, by inhibited lysosomal degradation of phagocytized substrates. All results persisted when cells were treated with both MOR and a commonly prescribed ART cocktail, suggesting minimal impact of ART during opioid exposure. We then performed mass spectrometry in HIV-infected MDMs treated with or without MOR to determine proteomic changes that suggest additional mechanisms by which opioids affect macrophage homeostasis. Using downstream pathway analyses, we found that MOR dysregulates ER quality control and extracellular matrix invasion. Our data indicate that MOR enhances inflammatory functions and impacts additional cellular processes in HIV-infected MDMs to potentially increases neuropathogenesis in PWH using opioids.
    Mesh-Begriff(e) Humans ; HIV Infections/metabolism ; Morphine/pharmacology ; Morphine/metabolism ; Analgesics, Opioid/pharmacology ; Analgesics, Opioid/metabolism ; Heroin/metabolism ; Heroin/pharmacology ; Quality of Life ; Reactive Oxygen Species/metabolism ; Proteomics ; Macrophages/metabolism ; Receptors, Opioid/metabolism
    Chemische Substanzen Morphine (76I7G6D29C) ; Analgesics, Opioid ; Heroin (70D95007SX) ; Reactive Oxygen Species ; Receptors, Opioid
    Sprache Englisch
    Erscheinungsdatum 2022-10-07
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.3MA0522-273RR
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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