Removal Of Histones Research Articles

Anp32e protects against accumulation of H2A.Z at Sox motif containing promoters during zebrafish gastrulation

Epigenetic regulation of chromatin states is crucial for proper gene expression programs and progression during development, but precise mechanisms by which epigenetic factors influence differentiation remain poorly understood. Here we find that the histone variant H2A.Z accumulates at Sox motif-containing promoters during zebrafish gastrulation while neighboring genes become transcriptionally active. These changes coincide with reduced expression of anp32e, the H2A.Z histone removal chaperone, suggesting that loss of Anp32e may lead to increases in H2A.Z binding during differentiation. Remarkably, genetic removal of Anp32e in embryos leads to H2A.Z accumulation prior to gastrulation and developmental genes become precociously active. Accordingly, H2A.Z accumulation occurs most extensively at Sox motif-associated genes, including many which are normally activated following gastrulation. Altogether, our results provide compelling evidence for a mechanism in which Anp32e preferentially restricts H2A.Z accumulation at Sox motifs to regulate the initial phases of developmental differentiation in zebrafish.

Spermatozoa in mice lacking the nucleoporin NUP210L show defects in head shape and motility but not in nuclear compaction or histone replacement.

Biallelic loss-of-function mutation of NUP210L, encoding a testis-specific nucleoporin, has been reported in an infertile man whose spermatozoa show uncondensed heads and histone retention. Mice with a homozygous transgene intronic insertion in Nup210l were infertile but spermatozoa had condensed heads. Expression from this insertion allele is undefined, however, and residual NUP210L production could underlie the milder phenotype. To resolve this issue, we have created Nup210lem1Mjmm , a null allele of Nup210l, in the mouse. Nup210lem1Mjmm homozygotes show uniform mild anomalies of sperm head morphology and decreased motility, but nuclear compaction and histone removal appear unaffected. Thus, our mouse model does not support that NUP210L loss alone blocks spermatid nuclear compaction. Re-analyzing the patient's exome data, we identified a rare, potentially pathogenic, heterozygous variant in nucleoporin gene NUP153 (p.Pro485Leu), and showed that, in mouse and human, NUP210L and NUP153 colocalize at the caudal nuclear pole in elongating spermatids and spermatozoa. Unexpectedly, in round spermatids, NUP210L and NUP153 localisation differs between mouse (nucleoplasm) and human (nuclear periphery). Our data suggest two explanations for the increased phenotypic severity associated with NUP210L loss in human compared to mouse: a genetic variant in human NUP153 (p.Pro485Leu), and inter-species divergence in nuclear pore function in round spermatids.

Histone removal in sperm protects paternal chromosomes from premature division at fertilization.

The global replacement of histones with protamines in sperm chromatin is widespread in animals, including insects, but its actual function remains enigmatic. We show that in the Drosophila paternal effect mutant paternal loss (pal), sperm chromatin retains germline histones H3 and H4 genome wide without impairing sperm viability. However, after fertilization, pal sperm chromosomes are targeted by the egg chromosomal passenger complex and engage into a catastrophic premature division in synchrony with female meiosis II. We show that pal encodes a rapidly evolving transition protein specifically required for the eviction of (H3-H4)2 tetramers from spermatid DNA after the removal of H2A-H2B dimers. Our study thus reveals an unsuspected role of histone eviction from insect sperm chromatin: safeguarding the integrity of the male pronucleus during female meiosis.

The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.

To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs). AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. The role of SET Domain Bifurcated Histone Lysine Methyltransferase 2 (SETDB2) in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. Single-cell RNA sequencing of human AAA tissues identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared with controls. Mechanistically, interferon-β regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription pathway with an FDA-approved inhibitor, Tofacitinib, limited SETDB2 expression in aortic macrophages. These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.

The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis.

Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.

DOT1L regulates chromatin reorganization and gene expression during sperm differentiation

Spermatozoa have a unique genome organization. Their chromatin is almost completely devoid of histones and is formed instead of protamines, which confer a high level of compaction and preserve paternal genome integrity until fertilization. Histone‐to‐protamine transition takes place in spermatids and is indispensable for the production of functional sperm. Here, we show that the H3K79‐methyltransferase DOT1L controls spermatid chromatin remodeling and subsequent reorganization and compaction of the spermatozoon genome. Using a mouse model in which Dot1l is knocked‐out (KO) in postnatal male germ cells, we found that Dot1l‐KO sperm chromatin is less compact and has an abnormal content, characterized by the presence of transition proteins, immature protamine 2 forms and a higher level of histones. Proteomic and transcriptomic analyses performed on spermatids reveal that Dot1l‐KO modifies the chromatin prior to histone removal and leads to the deregulation of genes involved in flagellum formation and apoptosis during spermatid differentiation. As a consequence of these chromatin and gene expression defects, Dot1l‐KO spermatozoa have less compact heads and are less motile, which results in impaired fertility.

Molecular Mechanisms of Neutrophil Extracellular Trap (NETs) Degradation

Although many studies have been exploring the mechanisms driving NETs formation, much less attention has been paid to the degradation and elimination of these structures. The NETs clearance and the effective removal of extracellular DNA, enzymatic proteins (neutrophil elastase, proteinase 3, myeloperoxidase) or histones are necessary to maintain tissue homeostasis, to prevent inflammation and to avoid the presentation of self-antigens. The persistence and overabundance of DNA fibers in the circulation and tissues may have dramatic consequences for a host leading to the development of various systemic and local damage. NETs are cleaved by a concerted action of extracellular and secreted deoxyribonucleases (DNases) followed by intracellular degradation by macrophages. NETs accumulation depends on the ability of DNase I and DNAse II to hydrolyze DNA. Furthermore, the macrophages actively engulf NETs and this event is facilitated by the preprocessing of NETs by DNase I. The purpose of this review is to present and discuss the current knowledge about the mechanisms of NETs degradation and its role in the pathogenesis of thrombosis, autoimmune diseases, cancer and severe infections, as well as to discuss the possibilities for potential therapeutic interventions. Several anti-NETs approaches had therapeutic effects in animal models of cancer and autoimmune diseases; nevertheless, the development of new drugs for patients needs further study for an effective development of clinical compounds that are able to target NETs.

The Ku complex promotes DNA end-bridging and this function is antagonized by Tel1/ATM kinase.

DNA double-strand breaks (DSBs) can be repaired by either homologous recombination (HR) or non-homologous end-joining (NHEJ). NHEJ is induced by the binding to DSBs of the Ku70-Ku80 heterodimer, which acts as a hub for the recruitment of downstream NHEJ components. An important issue in DSB repair is the maintenance of the DSB ends in close proximity, a function that in yeast involves the MRX complex and Sae2. Here, we provide evidence that Ku contributes to keep the DNA ends tethered to each other. The ku70-C85Y mutation, which increases Ku affinity for DNA and its persistence very close to the DSB ends, enhances DSB end-tethering and suppresses the end-tethering defect of sae2Δ cells. Impairing histone removal around DSBs either by eliminating Tel1 kinase activity or nucleosome remodelers enhances Ku persistence at DSBs and DSB bridging, suggesting that Tel1 antagonizes the Ku function in supporting end-tethering by promoting nucleosome removal and possibly Ku sliding inwards. As Ku provides a block to DSB resection, this Tel1 function can be important to regulate the mode by which DSBs are repaired.

MO283: A Novel Hemoperfusion Adsorbent for Selective Removal of Circulating Histones in Septic Blood

Abstract BACKGROUND AND AIMS Circulating histones play a crucial role in the development and progression of sepsis and is associated with high mortality. Hemadsorption with the CytoSorb® filter has been shown to non-specifically eliminate systemic circulating histones in plasma from injured patients ex vivo and in vitro. The aim of this study was to fabricate another novel hemoperfusion adsorbent for selective removal of histones in the blood of septic patients. METHOD Chitosan-cellulose composite hydrogels (CSCE) were first prepared using a liquid-liquid inversion method. Then, negatively charged heparin was grafted onto the surfaces of the CSCE hydrogels by EDC chemistry to obtain the histone sorbents (CSCEHEP hydrogels). The chemical structure of CSCEHEP hydrogels was characterized by Fourier transform infrared spectroscopy (FTIR) and its hemocompatibility was evaluated. The adsorption capacity and adsorption selectivity of CSCEHEP hydrogels for histone were then analysed by BCA protein quantitative method. Besides, the antagonistic effect of CSCEHEP hydrogels on histone-induced cytotoxicity was verified by in vitro cell experiments using HK-2 cell lines. RESULTS The obtained CSCEHEP hydrogels showed characteristic adsorption peaks of the sulfonic group at 1217 and 940 cm-1 in their FTIR spectrum, suggesting the successful immobilization of heparin onto the surface of the sorbent. The clotting time of plasma after a 30-min incubation with CSCEHEP hydrogels was significantly prolonged by 3 times while no obvious hemolysis, platelet activation, complement activation and other blood-material adverse reactions occurred during this incubation. With a heparin grafting, the adsorption capacity of CSCEHEP hydrogels towards histones (from calf thymus) increased significantly to 314.3 μg/g, with a clearance rate of 62.8%, compared to that of pristine CSCE, which is dependent on the initial histone concentrations in testing solutions. On the contrary, the adsorption capacity of bovine serum albumin by CSCEHEP hydrogels was significantly lower than that of histones, suggesting that the adsorption process of histone by CSCEHEP in plasma was selective. Meanwhile, CSCEHEP hydrogels significantly antagonized histone-induced cytotoxicity by binding histones, and the cell viability increased significantly from 47.1% (model group) to 72.0% (CSCEHEP-treat group). CONCLUSION CSCEHEP hydrogels are of good hemocompatibility and can effectively adsorb histones in PBS solution and antagonize histone-induced cytotoxicity. It is believed that the use of such a histone sorbent for extracorporeal blood purification may provide a novel insight into the modulation of aberrant immune responses in patients with sepsis.

NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer

Simple SummaryThe functional characterization of the BRD4-NUT fusion protein as the driver of the highly aggressive NUT Carcinoma is fundamental to the understanding of the mechanisms responsible for the genome-wide hyperacetylation of histones prior to their eviction during the final stages of sperm cells maturation.In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the oncogenic BRD4-NUT fusion protein in NUT carcinoma (NC) cells has proven to be essential in uncovering the mechanisms underlying histone hyperacetylation in spermatogenic cells. Indeed, these studies have revealed the mechanism by which a cooperation between BRD4, a bromodomain factor of the BET family, NUT, a normally testis-specific factor, and the histone acetyltransferase p300, induces the generation of hyperacetylated chromatin domains which are present in NC cells. The generation of Nut ko mice enabled us to demonstrate a genetic interaction between Nut and Brdt, encoding BRDT, a testis-specific BRD4-like factor. Indeed, in spermatogenic cells, NUT and p300 interact, which results in an increased acetylation of histone H4 at both positions K5 and K8. These two positions, when both acetylated, are specifically recognized by the first bromodomain of BRDT, which then mediates the removal of histone and their replacement by protamines. Taken together, these investigations show that the fusion of NUT to BRD4 in NUT Carcinoma cells reconstitutes, in somatic cells, a functional loop, which normally drives histone hyperacetylation and chromatin binding by a BET factor in spermatogenic cells.

Towards continuous mAb purification: Clearance of host cell proteins from CHO cell culture harvests via "flow-through affinity chromatography" using peptide-based adsorbents.

The growth of advanced analytics in manufacturing monoclonal antibodies (mAbs) has highlighted the challenges associated with the clearance of host cell proteins (HCPs). Of special concern is the removal of "persistent" HCPs, including immunogenic and mAb-degrading proteins, that co-elute from the Protein A resin and can escape the polishing steps. Responding to this challenge, we introduced an ensemble of peptide ligands that target the HCPs in Chinese hamster ovary (CHO) cell culture fluids and enable mAb purification via flow-through affinity chromatography. This study describes their integration into LigaGuard™, an affinity adsorbent featuring an equilibrium binding capacity of ~30 mg of HCPs per mLof resin as well as dynamic capacities up to 16 and 22 mg/mlat 1- and 2-minresidence times, respectively. When evaluated against cell culture harvests with different mAb and HCP titers and properties, LigaGuard™ afforded high HCP clearance, with logarithmic removal values (LRVs) up to 1.5, and mAb yield above 90%. Proteomic analysis of the effluents confirmed the removal of high-risk HCPs, including cathepsins, histones, glutathione-S transferase, and lipoprotein lipases. Finally, combining LigaGuard™ for HCP removal with affinity adsorbents for product capture afforded a global mAb yield of 85%, and HCP and DNA LRVs > 4.

Fluorescence approaches for biochemical analysis of ATP-dependent chromatin remodeling enzymes.

The dynamic nature of chromatin is an essential mechanism by which gene expression is regulated. Chromatin is comprised of nucleosomes, an octamer of histone proteins wrapped by DNA, and manipulation of these structures is carried out by a family of proteins known as ATP-dependent chromatin remodeling enzymes. These enzymes carry out a diverse range of activities, from appropriately positioning and adjusting the density of nucleosomes on genes, to installation and removal of histones for sequence variants, to ejection from DNA. These activities have a critical role in the proper maintenance of chromatin architecture, and dysregulation of chromatin remodeling is directly linked to the pathophysiology of various diseases. Mechanistic understanding of chromatin remodeling enzymes is therefore desirable, both as the drivers of this essential cellular activity and as potentially novel therapeutic targets in disease. In this chapter we cover our current methods for characterization of remodeler substrate binding affinity and catalytic activity, leveraging fluorescence polarization and Förster resonance energy transfer assays.

KAT5 histone acetyltransferase mutations in cancer cells.

Cancer cells are characterized by accumulation of mutations due to improperly repaired DNA damage. The DNA double strand break is one of the most severe form of damage and several redundant mechanisms have evolved to facilitate accurate repair. During DNA replication and in mitosis, breaks are primarily repaired by homologous recombination which is facilitated by several genes. Key to this process is the breast cancer susceptibility genes BRCA1 and BRCA2 as well as the accessory RAD52 gene. Proper chromatin remodeling is also essential for repair and the KAT5 histone acetyltransferase facilitates histone removal at the break. Here we undertook a pan cancer analysis to investigate mutations within the KAT5 gene in cancer cells. We employed two standard artificial algorithms to classify mutations as either driver (CHASMPlus algorithm) or pathogenic (VEST4 algorithm). We find that most predicted driver and disease-causing mutations occur in the catalytic site or within key regulatory domains. In silico analysis of protein structure using AlphaFold shows that these mutations are likely to destabilize the function of KAT5 or interactions with DNA or its other partners. The data presented here, although preliminary, could be used to inform clinical strategies.

UBR7 acts as a histone chaperone for post-nucleosomal histone H3.

Histone chaperones modulate the stability of histones beginning from histone synthesis, through incorporation into DNA, and during recycling during transcription and replication. Following histone removal from DNA, chaperones regulate histone storage and degradation. Here, we demonstrate that UBR7 is a histone H3.1 chaperone that modulates the supply of pre-existing post-nucleosomal histone complexes. We demonstrate that UBR7 binds to post-nucleosomal H3K4me3 and H3K9me3 histones via its UBR box and PHD. UBR7 binds to the non-nucleosomal histone chaperone NASP. In the absence of UBR7, the pool of NASP-bound post-nucleosomal histones accumulate and chromatin is depleted of H3K4me3-modified histones. We propose that the interaction of UBR7 with NASP and histones opposes the histone storage functions of NASP and that UBR7 promotes reincorporation of post-nucleosomal H3 complexes.

Chaperoning histones at the DNA repair dance

Unlike all other biological molecules that are degraded and replaced if damaged, DNA must be repaired as chromosomes cannot be replaced. Indeed, DNA endures a wide variety of structural damage that need to be repaired accurately to maintain genomic stability and proper functioning of cells and to prevent mutation leading to disease. Given that the genome is packaged into chromatin within eukaryotic cells, it has become increasingly evident that the chromatin context of DNA both facilitates and regulates DNA repair processes. In this review, we discuss mechanisms involved in removal of histones (chromatin disassembly) from around DNA lesions, by histone chaperones and chromatin remodelers, that promotes accessibility of the DNA repair machinery. We also elaborate on how the deposition of core histones and specific histone variants onto DNA (chromatin assembly) during DNA repair promotes repair processes, the role of histone post translational modifications in these processes and how chromatin structure is reestablished after DNA repair is complete.

Dpb4 promotes resection of DNA double-strand breaks and checkpoint activation by acting in two different protein complexes

Budding yeast Dpb4 (POLE3/CHRAC17 in mammals) is a highly conserved histone fold protein that is shared by two protein complexes: the chromatin remodeler ISW2/hCHRAC and the DNA polymerase ε (Pol ε) holoenzyme. In Saccharomyces cerevisiae, Dpb4 forms histone-like dimers with Dls1 in the ISW2 complex and with Dpb3 in the Pol ε complex. Here, we show that Dpb4 plays two functions in sensing and processing DNA double-strand breaks (DSBs). Dpb4 promotes histone removal and DSB resection by interacting with Dls1 to facilitate the association of the Isw2 ATPase to DSBs. Furthermore, it promotes checkpoint activation by interacting with Dpb3 to facilitate the association of the checkpoint protein Rad9 to DSBs. Persistence of both Isw2 and Rad9 at DSBs is enhanced by the A62S mutation that is located in the Dpb4 histone fold domain and increases Dpb4 association at DSBs. Thus, Dpb4 exerts two distinct functions at DSBs depending on its interactors.

The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphology by regulating steady-state H2A.Z binding in neurons.

SUMMARYRapid removal of histone H2A.Z from neuronal chromatin is a key step in learning-induced gene expression and memory formation, but mechanisms underlying learning-induced H2A.Z removal are unclear. Anp32e was recently identified as an H2A.Z-specific histone chaperone that removes H2A.Z from nucleosomes in dividing cells, but its role in non-dividing neurons is unclear. Moreover, prior studies investigated Anp32e function under steady-state rather than stimulus-induced conditions. Here, we show that Anp32e regulates H2A.Z binding in neurons under steady-state conditions, with lesser impact on stimulus-induced H2A.Z removal. Functionally, Anp32e depletion leads to H2A.Z-dependent impairment in transcription and dendritic arborization in cultured hippocampal neurons, as well as impaired recall of contextual fear memory and transcriptional regulation. Together, these data indicate that Anp32e regulates behavioral and morphological outcomes by preventing H2A.Z accumulation in chromatin rather than by regulating activity-mediated H2A.Z dynamics.

Distinct spermiogenic phenotypes underlie sperm elimination in the Segregation Distorter meiotic drive system.

Segregation Distorter (SD) is a male meiotic drive system in Drosophila melanogaster. Males heterozygous for a selfish SD chromosome rarely transmit the homologous SD+ chromosome. It is well established that distortion results from an interaction between Sd, the primary distorting locus on the SD chromosome and its target, a satellite DNA called Rsp, on the SD+ chromosome. However, the molecular and cellular mechanisms leading to post-meiotic SD+ sperm elimination remain unclear. Here we show that SD/SD+ males of different genotypes but with similarly strong degrees of distortion have distinct spermiogenic phenotypes. In some genotypes, SD+ spermatids fail to fully incorporate protamines after the removal of histones, and degenerate during the individualization stage of spermiogenesis. In contrast, in other SD/SD+ genotypes, protamine incorporation appears less disturbed, yet spermatid nuclei are abnormally compacted, and mature sperm nuclei are eventually released in the seminal vesicle. Our analyses of different SD+ chromosomes suggest that the severity of the spermiogenic defects associates with the copy number of the Rsp satellite. We propose that when Rsp copy number is very high (> 2000), spermatid nuclear compaction defects reach a threshold that triggers a checkpoint controlling sperm chromatin quality to eliminate abnormal spermatids during individualization.

RNF8 is not required for histone-to-protamine exchange in spermiogenesis†.

While an E3 ubiquitin ligase, RNF8, was initially reported to be required for histone-to-protamine exchange in spermiogenesis, we subsequently demonstrated that RNF8 is not involved in this process. Nevertheless, reflecting a lingering misunderstanding in the field, a growing number of studies have continued to postulate a requirement for RNF8 in the histone-to-protamine exchange. For example, a recent study claimed that a mouse PIWI protein, MIWI, controls RNF8-mediated histone-to-protamine exchange. Here, confirming our earlier conclusions, we show that RNF8 is required neither for the establishment of histone H4K16 acetylation, which is an initial step in histone removal during spermiogenesis, nor for the incorporation of two protamine proteins, PRM1 and PRM2. Thus, whereas RNF8 mediates ubiquitination of H2A on the sex chromosomes in meiosis, during the prior stage of spermatogenesis, our genetic evidence underscores that RNF8 is not involved in histone-to-protamine exchange.

Natural catalytic immunoglobulins hydrolyzing histones as a link between inflammation and humoral immunity in schizophrenia

IntroductionSchizophrenia pathogenesis is known to be associated with chronic low-grade inflammation. Inflammation can be caused by extracellular histones that are released from cells due to apoptosis dysfunction. It can also be accompanied by the formation of natural catalytic immunoglobulins that bind and hydrolyze histones.ObjectivesTo investigate the ability to hydrolyze various histones by polyclonal IgGs from serum of patients with schizophrenia.MethodsWe recruited 50 patients (28 men and 22 women) with a verified diagnosis of paranoid or simple schizophrenia and 25 healthy individuals (13 men and 12 women) in our study. IgG preparations were obtained by affinity chromatography and analyzed by SDS-PAGE and MALDI MS. Catalytic activity of IgGs were revealed by the degree of hydrolysis of five histones using SDS-PAGE. To prove that antibodies exhibit histone-hydrolyzing activity, we used rigorous generally accepted criteria. Statistical analysis was performed in Origin 2019.ResultsIgGs of patients are shown to bind and hydrolyze various histones with high efficiencies. The IgGs histone-hydrolyzing activity level, depending on the type of histone (H1, H2a, H2b, H3, H4), was statistically significantly 6–20 times higher than that of healthy individuals (Fig. 1). However, only 21% of patients with schizophrenia had IgGs with very high activity. The IgGs activity level correlated with PANSS General scale.Fig.1. Histone-hydrolyzing activity of IgG.ConclusionsWe suggest that histone-hydrolyzing antibodies may play a compensatory role in schizophrenia because removal of extracellular histones minimizes the inflammatory responses. Therefore, such IgGs may be the link between inflammation and humoral immunity, and also be a promising biomarker.Conflict of interestThis work was supported by Russian Foundation for Basic Research under grant 20-015-00156. E.A.E. is the recipient of the fellowship of the President of the Russian Federation (SP-2258.2019.4).