Protein arginine methyltransferases (PRMTs) catalyze arginine methylation on both chromatin-bound and cytoplasmic proteins. Accumulating evidence supports the involvement of PRMT5, the major type II ...PRMT, in cell survival and differentiation pathways that are important during development and in tumorigenesis. PRMT5 is an attractive drug target in various cancers, and inhibitors are currently in oncological clinical trials. Nonetheless, given the complex biology of PRMT5 and its multiple nonhistone substrates, it is paramount to fully characterize these dynamic changes in methylation and to link them to the observed anticancer effects to fully understand the functions of PRMT5 and the consequences of its inhibition. Here, we used a newly established pipeline coupling stable isotope labeling with amino acids in cell culture (SILAC) with immunoenriched methyl peptides to globally profile arginine monomethylation and symmetric dimethylation after PRMT5 inhibition by a selective inhibitor. We adopted heavy methyl SILAC as an orthogonal validation method to reduce the false discovery rate. Through in vitro methylation assays, we validated a set of PRMT5 targets identified by mass spectrometry and provided previously unknown mechanistic insights into the preference of the enzyme to methylate arginine sandwiched between two neighboring glycines (a Gly-Arg-Gly, or "GRG," sequence). Our analysis led to the identification of previously unknown PRMT5 substrates, thus both providing insight into the global effects of PRMT5 and its inhibition in live cells, beyond chromatin, and refining our knowledge of its substrate specificity.
The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We ...characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.
O-linked N-acetylglucosamine (O-GlcNAc) transferase (Ogt) activity is essential for embryonic stem cell (ESC) viability and mouse development. Ogt is present both in the cytoplasm and the nucleus of ...different cell types and catalyzes serine and threonine glycosylation. We have characterized the biochemical features of nuclear Ogt and identified the ten-eleven translocation (TET) proteins Tet1 and Tet2 as stable partners of Ogt in the nucleus of ESCs. We show at a genome-wide level that Ogt preferentially associates with Tet1 to genes promoters in close proximity of CpG-rich transcription start sites. These regions are characterized by low levels of DNA modification, suggesting a link between Tet1 and Ogt activities in regulating CpG island methylation. Finally, we show that Tet1 is required for binding of Ogt to chromatin affecting Tet1 activity. Taken together, our data characterize how O-GlcNAcylation is recruited to chromatin and interacts with the activity of 5-methylcytosine hydroxylases.
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► Ogt forms a complex with Tet1 and Tet2 in the nucleus of embryonic stem cells ► Ogt preferentially associates with promoter regions in proximity of TSS ► Ogt shows >90% of colocalization with Tet1 at methylation-free CpG-rich elements ► Tet1 is required for global Ogt chromatin recruitment regulating its activity
The enzymes of the poly-ADP-ribose polymerase (PARP) superfamily control many relevant cellular processes, but a precise understanding of their activities in different physiological or disease ...contexts is largely incomplete. We found that transcription of several
genes was dynamically regulated upon murine macrophage activation by endotoxin. PARP14 was strongly induced by several inflammatory stimuli and translocated into the nucleus of stimulated cells. Quantitative mass spectrometry analysis showed that PARP14 bound to a group of IFN-stimulated gene (ISG)-encoded proteins, most with an unknown function, and it was required for their nuclear accumulation. Moreover, PARP14 depletion attenuated transcription of primary antiviral response genes regulated by the IFN regulatory transcription factor 3, including
, thus reducing IFN-β production and activation of ISGs involved in the secondary antiviral response. In agreement with the above-mentioned data, PARP14 hindered
proliferation in murine macrophages. Overall, these data hint at a role of PARP14 in the control of antimicrobial responses and specifically in nuclear activities of a subgroup of ISG-encoded proteins.
The novel coronavirus pandemic calls for a rapid adaptation of conventional medical practices to meet the evolving needs of such vulnerable patients. People with coronavirus disease (COVID-19) may ...frequently require treatment with psychotropic medications, but are at the same time at higher risk for safety issues because of the complex underlying medical condition and the potential interaction with medical treatments.
In order to produce evidence-based practical recommendations on the optimal management of psychotropic medications in people with COVID-19, an international, multi-disciplinary working group was established. The methodology of the WHO Rapid Advice Guidelines in the context of a public health emergency and the principles of the AGREE statement were followed. Available evidence informing on the risk of respiratory, cardiovascular, infective, hemostatic, and consciousness alterations related to the use of psychotropic medications, and drug-drug interactions between psychotropic and medical treatments used in people with COVID-19, was reviewed and discussed by the working group.
All classes of psychotropic medications showed potentially relevant safety risks for people with COVID-19. A set of practical recommendations was drawn in order to inform frontline clinicians on the assessment of the anticipated risk of psychotropic-related unfavorable events, and the possible actions to take in order to effectively manage this risk, such as when it is appropriate to avoid, withdraw, switch, or adjust the dose of the medication.
The present evidence-based recommendations will improve the quality of psychiatric care in people with COVID-19, allowing an appropriate management of the medical condition without worsening the psychiatric condition and vice versa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
More than 500 kinases are implicated in the control of most cellular process in mammals, and deregulation of their activity is linked to cancer and inflammatory disorders. 80 clinical kinase ...inhibitors (CKIs) have been approved for clinical use and hundreds are in various stages of development. However, CKIs inhibit other kinases in addition to the intended target(s), causing both enhanced clinical effects and undesired side effects that are only partially predictable based on in vitro selectivity profiling. Here, we report an integrative approach grounded on the use of chromatin modifications as unbiased, information-rich readouts of the functional effects of CKIs on macrophage activation. This approach exceeded the performance of transcriptome-based approaches and allowed us to identify similarities and differences among CKIs with identical intended targets, to recognize novel CKI specificities and to pinpoint CKIs that may be repurposed to control inflammation, thus supporting the utility of this strategy to improve selection and use of CKIs in clinical settings.
Synopsis
Unbiased genome-wide analyses of epigenomic alterations induced by clinical kinase inhibitors (CKIs) in macrophages activated by inflammatory stimuli allow identifying insofar unknown similarities and differences among CKIs, improving their annotations and showing opportunities for repurposing.
A genome-wide analysis was developed that exploits epigenetic changes as unbiased, high-content and information-rich read-outs of CKIs’ effects.
Effects of CKIs on epigenomic changes induced by macrophage activation can be explained by drug-specific combinations of on-target and off-target effects on different sets of signal-regulated transcription factors.
CKIs with similar intended annotated target(s) show only partially overlapping epigenomic effects.
Conversely, similarities among CKIs with distinct annotations indicate opportunities for drug repurposing.
An epigenomic readout was shown to exceed transcription-based analyses in capturing functional effects of CKIs and similarities among them.
Unbiased genome-wide analyses of epigenomic alterations induced by clinical kinase inhibitors (CKIs) in macrophages activated by inflammatory stimuli allow identifying insofar unknown similarities and differences among CKIs, improving their annotations and showing opportunities for repurposing.
The Yin Yang 1 (YY1) transcription factor is a master regulator of development, essential for early embryogenesis and adult tissues formation. YY1 is the mammalian orthologue of Pleiohomeotic, one of ...the transcription factors that binds Polycomb DNA response elements in Drosophila melanogaster and mediates Polycomb group proteins (PcG) recruitment to DNA. Despite several publications pointing at YY1 having a similar role in mammalians, others showed features of YY1 that are not compatible with PcG functions. Here, we show that, in mouse Embryonic Stem (ES) cells, YY1 has genome-wide PcG-independent activities while it is still stably associated with the INO80 chromatin-remodeling complex, as well as with novel RNA helicase activities. YY1 binds chromatin in close proximity of the transcription start site of highly expressed genes. Loss of YY1 functions preferentially led to a down-regulation of target genes expression, as well as to an up-regulation of several small non-coding RNAs, suggesting a role for YY1 in regulating small RNA biogenesis. Finally, we found that YY1 is a novel player of Myc-related transcription factors and that its coordinated binding at promoters potentiates gene expression, proposing YY1 as an active component of the Myc transcription network that links ES to cancer cells.
The integration of endocytic routes is critical to regulate receptor signaling. A nonclathrin endocytic (NCE) pathway of the epidermal growth factor receptor (EGFR) is activated at high ligand ...concentrations and targets receptors to degradation, attenuating signaling. Here we performed an unbiased molecular characterization of EGFR-NCE.We identified NCE-specific regulators, including the endoplasmic reticulum (ER)–resident protein reticulon 3 (RTN3) and a specific cargo, CD147. RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)–ER contact sites that were required for the formation and/or maturation of NCE invaginations. Ca2+ release at these sites, triggered by inositol 1,4,5-trisphosphate (IP₃)–dependent activation of ER Ca2+ channels, was needed for the completion of EGFR internalization. Thus, we identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca2+ signaling.
Several lines of research suggest that reproductive-related hormonal events may affect the course of bipolar disorder in some women. However, data on associations between bipolar disorder and ...menarche, menstrual cycle, and menopause are mixed. This article reviews the literature on the potential effects of menarche, menstrual cycle, and menopause on bipolar disorder.
A narrative review of published articles on bipolar disorder and menstrual cycle events was conducted. The primary outcome assessed was the impact of menarche, menstrual cycle and menopause on the course of bipolar illness. Databases searched were PubMed, Ovid, Scopus, PsycINFO, Medline, and Cochrane Libraries from inception to August 2021.
Twenty-two studies were identified and included in the narrative synthesis. Research suggested that a subset of women with bipolar disorder are vulnerable to the impact of menstrual cycle events. Menarche seems to be associated with age at onset of bipolar illness especially in case of bipolar disorder type I and the specific age at menarche may predict some clinical features of the disorder. Menstrual cycle likely affects the course of bipolar disorder but the pattern of mood variability is not clear. Menopause appears to be not only a period of vulnerability to mood alteration, especially depressive episodes, and impairment of quality of life, but also a potential trigger of bipolar illness onset.
The impact of menarche, menstrual cycle, and menopause on bipolar disorder is largely understudied. Preliminary evidence suggests that a subset of women with bipolar disorder may have their mood shifts affected by menstrual cycle events, with different patterns depending on the type of bipolar disorder also. Further researches are needed to deep the impact of menarche, menstrual cycle, and menopause on bipolar illness.
Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially ...devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents’ quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.
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