Biology subjects

Wei, Y.

Publications and source records attributed to Wei, Y..

At least 271 records · Page 15Linked to original sources

bioRxiv2020

Epigenetic Consequences of Hormonal Interactions between Opposite-sex Twin Fetuses

In human opposite-sex twins, certain phenotypic traits of the female are affected negatively by testosterone transfer from the male, while the male may or may not be affected by the female in utero. However, no study was carried out to uncover the epigenetic basis of these effects. Here, we generated DNA methylation data from 54 newborn twins and histone modification data from 14 newborn twins, including female-female (FF), female-male (FM), and male-male (MM) newborn twins, to exclude the effects of postnatal environment and socialization, and investigated the epigenetic consequences of prenatal interactions between female and male gonadal hormones. We found that FM-Fs (female in FM twins) were distinguishable from FF twins by their DNA methylome, as were FM-Ms (male in FM twins) from MM twins. The correlation between genome-wide DNA methylation of females and males showed that FM-Fs, but not FFs, were closer to males from FM-Ms and MMs. Interestingly, the DNA methylomic differences between FM-Fs and FFs, but not those between FM-Ms and MMs, were linked to cognition and the nervous system. Meanwhile, FM-Ms and MMs, but not FM-Fs and FFs, displayed differential histone modification of H3K4me3, which were linked to immune responses. These findings provide epigenetic evidence for the twin testosterone transfer hypothesis and explain how prenatal hormone exposure is linked to reported and novel traits of childhood and adult through the epigenome in opposite-sex twins. Author SummaryPrenatal exposure to testosterone may affect physiological, cognitive, and behavioral traits in females with male co-twins, while the males in opposite-sex twins present weak and inconsistent influences. In this study, we systematically investigated the hormonal interactions between opposite-sex twins in newborns from epigenetics including DNA methylation and histone modifications. We show that DNA methylome in FM-Fs (female in FM twins) was different from FF twins and their DNA methylomic differences were associated with cognition and the nervous system. We also suggest that FM-Ms (male in FM twins) were distinguishable from MM twins by their DNA methylome and FM-Ms versus MMs displayed differential histone modification of H3K4me3, which were linked to immune responses. Our study provides insight into the epigenetic explanation for hormonal influences between opposite-sex fetuses.

developmental biology↗

bioRxiv2020

IgY antibodies against Ebola virus possess post-exposure protection and excellent thermostability

Ebola virus (EBOV) is the most virulent pathogens that cause hemorrhagic fever with high mortality rates in humans and nonhuman primates. The postexposure antibody therapies to prevent EBOV infection are considered efficient. However, due to the poor thermal stability of mammalian antibody, their application in the tropics has been limited. Here, we developed a thermostable therapeutic antibody against EBOV based on chicken immunoglobulin Y (IgY). The IgY antibodies demonstrated excellent thermal stability, which retained their neutralizing activity at 25{degrees}C for one year, in contrast to conventional polyclonal or monoclonal antibodies (MAbs). We immunized laying hens with a variety of EBOV vaccine candidates and confirmed that VSV {Delta} G/EBOVGP encoding the EBOV glycoprotein could induce high titer neutralizing antibodies against EBOV. The therapeutic efficacy of immune IgY antibodies in vivo was evaluated in the newborn Balb/c mice model. Lethal dose of virus challenged mice were treated 2 or 24 h post-infection with different doses of anti-EBOV IgY. The group receiving a high dose of 106 NAU/kg (neutralizing antibody units/kilogram) achieved complete protection with no signs of disease, while the low-dose group was only partially protected. In contrast, all mice receiving naive IgY died within 10 days. In conclusion, the anti-EBOV IgY exhibits excellent thermostability and protective efficacy, and it is very promising to be developed as alternative therapeutic entities. Author SummaryAlthough several Ebola virus therapeutic antibodies have been reported in recent years, however, due to the poor thermal stability of mammalian antibody, their application in tropical endemic areas has been limited. We developed a highly thermostable therapeutic antibody against EBOV based on chicken immunoglobulin Y (IgY). The IgY antibodies demonstrated excellent thermal stability, which retained their neutralizing activity at 25{degrees}C for one year. The newborn mice receiving passive transfer of IgY achieved complete protection against a lethal dose of virus challenge indicating that the anti-EBOV IgY provides a promising countermeasure to solve the current clinical application problems of Ebola antibody-based treatments in Africa.

immunology↗

bioRxiv2020

Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

cell biology↗

bioRxiv2020

Developmentally Delayed Epigenetic Reprogramming Underlying the Pathogenesis of Preeclampsia

Preeclampsia, a life-threatening pregnancy complication characterized by hypertension and multiorgan damage, affects 2-5% of pregnancies and causes 76,000 deaths per year. Most preeclampsia associated syndromes immediately dispel after removal of placenta, indicating a casual role of placenta in the pathogenesis. Failed transformation of spiral artery due to insufficient invasion and excessive apoptosis of trophoblast suggested developmental defects in preeclampsia placenta. However, the underlying molecular mechanisms that affected placenta development in preeclampsia remained elusive. Here we show that, in preeclampsia placenta, the epigenetic landscape formed during extraembryonic tissue differentiation was disrupted: dramatic chromatin accessibility shift affected known and novel genes implicated in preeclampsia. DNA methylation defects in preeclampsia affected lineage-defining PcG-controlled loci in trophectoderm. LTR12 retrotransposons associated with VCT/SCT-specific genes were hypermethylated. Meanwhile, hundreds of PcG-regulated EVT-specific gene promoters, which otherwise undergone post-ZGA extraembryonic-tissue-specific de novo methylation, were hypomethylated and hyper-activated. Together, these epigenetic defects resulted in placenta developmental delay in preeclampsia. The defective methylation pattern could be detected in serum cfDNA, and could be used to accurately predict preeclampsia at early pregnancy weeks in independent validation cohorts. Our data suggests that the preeclampsia placenta represents a stalled state of epigenetic reprogramming en route of development from trophectoderm to normal placenta.

genomics↗

bioRxiv2020

Single-neuron models linking electrophysiology, morphology and transcriptomics across cortical cell types

Identifying the cell types constituting brain circuits is a fundamental question in neuroscience and motivates the generation of taxonomies based on electrophysiological, morphological and molecular single cell properties. Establishing the correspondence across data modalities and understanding the underlying principles has proven challenging. Bio-realistic computational models offer the ability to probe cause-and-effect and have historically been used to explore phenomena at the single-neuron level. Here we introduce a computational optimization workflow used for the generation and evaluation of more than 130 million single neuron models with active conductances. These models were based on 230 in vitro electrophysiological experiments followed by morphological reconstruction from the mouse visual cortex. We show that distinct ion channel conductance vectors exist that distinguish between major cortical classes with passive and h-channel conductances emerging as particularly important for classification. Next, using models of genetically defined classes, we show that differences in specific conductances predicted from the models reflect differences in gene expression in excitatory and inhibitory cell types as experimentally validated by single-cell RNA-sequencing. The differences in these conductances, in turn, explain many of the electrophysiological differences observed between cell types. Finally, we show the robustness of the herein generated single-cell models as representations and realizations of specific cell types in face of biological variability and optimization complexity. Our computational effort generated models that reconcile major single-cell data modalities that define cell types allowing for causal relationships to be examined. HighlightsO_LIGeneration and evaluation of more than 130 million single-cell models with active conductances along the reconstructed morphology faithfully recapitulate the electrophysiology of 230 in vitro experiments. C_LIO_LIOptimized ion channel conductances along the cellular morphology ( all-active) are characteristic of model complexity and offer enhanced biophysical realism. C_LIO_LIIon channel conductance vectors of all-active models classify transcriptomically defined cell-types. C_LIO_LICell type differences in ion channel conductances predicted by the models correlate with experimentally measured single-cell gene expression differences in inhibitory (Pvalb, Sst, Htr3a) and excitatory (Nr5a1, Rbp4) classes. C_LIO_LIA set of ion channel conductances identified by comparing between cell type model populations explain electrophysiology differences between these types in simulations and brain slice experiments. C_LIO_LIAll-active models recapitulate multimodal properties of excitatory and inhibitory cell types offering a systematic and causal way of linking differences between them. C_LI

neuroscience↗

bioRxiv2020

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

The conventional outflow pathway is a complex tissue responsible for maintaining intraocular pressure (IOP) homeostasis. The coordinated effort of multiple cells with differing responsibilities ensure healthy outflow function and IOP maintenance. Dysfunction of one or more resident cell type results in ocular hypertension and risk for glaucoma, a leading cause of blindness. In this study, single cell RNA sequencing was performed to generate a comprehensive cell atlas of human conventional outflow tissues. We obtained 17757 genes expression profiles from 8758 cells from eight eyes of four donors representing the outflow cell transcriptome. Upon clustering analysis, 12 distinct cell types were identified, and region-specific expression of candidate genes were mapped in human tissues. Significantly, we identified two distinct expression patterns (myofibroblast and fibroblast) from cells located in the trabecular meshwork (TM), the primary structural component of the conventional outflow pathway. We also located neuron and macrophage signatures in the TM. The second primary component structure, Schlemms canal displayed a unique combination of lymphatic/blood vascular gene expression. Other expression clusters corresponded to cells from neighboring tissues, predominantly in the ciliary muscle/scleral spur, which together correspond to the uveoscleral outflow path. Importantly, the utility of our atlas was demonstrated by mapping glaucoma-relevant genes to outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of conventional and unconventional outflow pathway structures responsible for IOP homeostasis. Significance statementOcular hypertension is the primary, and only modifiable risk factor for glaucoma, the leading cause of irreversible blindness. Intraocular pressure is regulated homeostatically by resistance to aqueous humor outflow through an architecturally complex tissue, the conventional/trabecular pathway. In this study, we generated a comprehensive cell atlas of the human trabecular meshwork and neighboring tissues using single cell, RNA sequencing. We identified 12 distinct cell types, and mapped region-specific expression of candidate genes. The utility of our atlas was demonstrated by mapping glaucoma-relevant genes to conventional outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of tissue structures responsible for intraocular pressure homeostasis in health, and dysregulation in disease.

cell biology↗

bioRxiv2020

Prediction of meiosis-essential genes based upon the dynamic proteomes responsive to spermatogenesis

Mammalian meiosis is a specific cell division process during sexual reproduction, whereas a comprehensive proteome of the different meiotic stages has not been systematically investigated. Here, we isolated different types of spermatocytes from the testes of spermatogenesis-synchronized mice and quantified the corresponding proteomes with high-resolution mass spectrometry. A total of 8,002 proteins were identified in nine types of germ cells, and the protein signatures of spermatogenesis were characterized using the dynamic proteomes. A supervised machine learning package, FuncProFinder, was developed to predict meiosis-essential candidate genes based on changes in their protein abundance. Of the candidates without functional annotation, four of the ten genes with the highest prediction scores, Zcwpw1, Tesmin, 1700102P08Rik, and Kctd19, were validated as meiosis-essential genes using knockout mouse models. The proteomic analysis of spermatogenic cells provides a solid foundation for studying the mechanism of mammalian meiosis.

developmental biology↗

bioRxiv2020

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics: a framework for tracking neurodegenerative disease

Cortical layer-specific ultra-high field MRI has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease. Here we compare cortical layer-specificity for a 7T multi-parametric mapping (MPM) 500m whole brain acquisition to the von Economo and Big Brain post-mortem histology atlases. We also investigate the relationship between 7T MPMs, layer-specific gene expression and Huntingtons disease related genes, using the Allen Human Brain atlas. Finally we link MPM cortical depth measures with white matter connections using high-fidelity diffusion tractography from a 300mT/m Connectom MRI system. We show that R2* across cortical depths is highly correlated with layer-specific cell number, cell staining intensity and gene expression. Furthermore white matter connections were highly correlated with grey matter R1 and R2* across cortical depths. These findings demonstrate the potential of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease.

neuroscience↗

bioRxiv2019

QTL Mapping and integration as well as candidate gene prediction for branch number in soybean

Branch number is an important factor that affects crop plant architecture and yield in soybean. With the aim of elucidating the genetic basis of branch number, we identified 10 consensus quantitative trait loci (QTLs) through preliminary mapping, which were on chromosome A1, B2, C1, C2, D1a, D1b, F, L and N, explained 0.3-33.3% of the phenotypic variance. Of these, three QTLs were identical to previously identified ones, whereas the other seven were novel. In addition, one major QTL-qBN.C2 (R2=33.3%) was detected in all three environments and another new major QTL-qBN.N (R2=19.6%) was detected in two environments (Taiyuan 2017 and Taiyuan 2018), but only in Taiyuan. Thus, the QTL x environment interaction analysis confirmed that QTL-qBN.N was strongly affected by the environment. We compared the physical positions of the QTL intervals of the candidate genes potentially involved in branching development, and five orthologous genes were ultimately selected and related to the establishment of axillae meristem organization and lateral organs, qBN.A1 (SoyZH13_05G177000.m1), qBN.C2 (SoyZH13_06G176500.m1, SoyZH13_06G185600.m1), and qBN.D1b-1 (SoyZH13_02G035400.m1, SoyZH13_02G070000.m3). The results of our study reveal a complex and relatively complete genetic architecture and can serve as a basis for the positional gene cloning of branch number in soybean.

genetics↗

bioRxiv2019

Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation

Dosage compensation between the sexes has emerged independently multiple times during evolution, often harnessing long noncoding RNAs (lncRNAs) to alter gene expression on the sex chromosomes. In eutherian mammals, X chromosome inactivation (XCI) in females proceeds via the lncRNA Xist, which coats one of the two X chromosomes and recruits repressive proteins to epigenetically silence gene expression in cis1,2. How Xist evolved new functional RNA domains to recruit ancient, pleiotropic protein partners is of great interest. Here we show that Spen, an Xist-binding repressor protein essential for XCI3-7, binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen inactivation leads to de-repression of a subset of endogenous retroviral (ERV) elements in embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing8-9. ERV RNA and Xist A-repeat bind the RRM3 domain of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in local gene silencing in cis. These results suggest that insertion of an ERV element into proto-Xist may have been a critical evolutionary event, which allowed Xist to coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.

genomics↗

bioRxiv2019

Structural modularity of the XIST ribonucleoprotein complex

Long noncoding RNAs are thought to regulate gene expression by organizing protein complexes through unclear mechanisms. XIST controls the inactivation of an entire X chromosome in female placental mammals. Here we develop and integrate several orthogonal structure-interaction methods to demonstrate that XIST RNA-protein complex folds into an evolutionarily conserved modular architecture. Chimeric RNAs and clustered protein binding in fRIP and eCLIP experiments align with long-range RNA secondary structure, revealing discrete XIST domains that interact with distinct sets of effector proteins. CRISPR-Cas9-mediated permutation of the Xist A-repeat location shows that A-repeat serves as a nucleation center for multiple Xist-associated proteins and m6A modification. Thus modular architecture plays an essential role, in addition to sequence motifs, in determining the specificity of RBP binding and m6A modification. Together, this work builds a comprehensive structure-function model for the XIST RNA-protein complex, and suggests a general strategy for mechanistic studies of large ribonucleoprotein assemblies.

molecular biology↗

bioRxiv2019

Epigenetic Effects of Assisted Reproductive Technology in Human Offspring

The births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the potential for elevated risks of ART-related disorders persists in adult life, and the underlying epigenetic mechanisms are largely uncharacterized. Here, we recruited 100 nuclear families and profiled the DNA methylomes, genome-wide histone modifications and transcriptomes to clarify the inherent extra risks attributable to specific ART procedures. We discovered that IVF-ET seemed to introduce less disturbance into the infant epigenome than IVF-FET or ICSI-ET did. Furthermore, we noted approximately half of the DNA methylomic changes in ART-conceived offspring could be explained by parental background biases. Through removal of the parental effect, we confirmed that ART per se would introduce minor DNA methylation changes locally. More importantly, we found that ART-induced epigenomic alterations were highly enriched in the processes which might contribute to increased incidence of preeclampsia during pregnancy and metabolic syndrome in offspring. Overall, our study provides an epigenetic basis for the potential long-term health risks in ART-conceived offspring that reinforces the need to review all methods of human ART.

genetics↗

bioRxiv2019

Single-Cell RNA-Seq Reveals Endocardial Defect in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is one of the most challenging forms of congenital heart diseases. Previous studies were mainly focused on intrinsic defects in myocardium. However, this does not sufficiently explain the abnormal development of the cardiac valve, septum, and vasculature, known to originate from the endocardium. Here, using single-cell RNA profiling, induced pluripotent stem cells, and human fetal heart tissue with an underdeveloped left ventricle, we identified a developmentally impaired endocardial population in HLHS. The intrinsic endocardial deficits contributed to abnormal endothelial to mesenchymal transition, NOTCH signaling, and extracellular matrix organization, all of which are key factors in valve formation. Consequently, endocardial abnormalities conferred reduced proliferation and maturation of cardiomyocytes through a disrupted fibronectin-integrin interaction. Several recently described HLHS de novo mutations were associated with abnormal endocardial gene and FN1 regulation and expression. Our studies provide a rationale for considering endocardial function in future regenerative strategies for HLHS.

developmental biology↗

bioRxiv2019

Differential protein metabolism and regeneration in hypertrophic diaphragm and atrophic gastrocnemius muscles in hibernating Daurian ground squirrels

Whether differences in regulation of protein metabolism and regeneration are involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA), fiber type distribution, and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1, and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1, and LC3-II), and muscle regeneration (MyoD, myogenin, and myostatin). Results showed the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4% in the hibernation group compared with the summer active group. Both muscles displayed a significant fast-to-slow fiber-type transition in hibernation. Our study further indicated that increased protein synthesis, decreased protein degradation, and increased muscle regeneration potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation, and decreased muscle regeneration potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism may contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.

physiology↗

bioRxiv2019

Broadly Conserved Roles of TMEM-131 Family Proteins in Intracellular Collagen Assembly and Secretory Cargo Trafficking

Collagen is the most abundant protein in animals. Its dysregulation contributes to ageing and human disorders including tissue fibrosis in major organs. How premature collagens in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNAi screen, we identified an uncharacterized C. elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. TMEM-131 N-termini contain bacterial PapD chaperone-like (PapD-L) domains essential for collagen assembly and secretion. Human TMEM131 binds to COL1A2 and TRAPPC8 via N-terminal PapD-L and C-terminal domain, respectively, to drive collagen production. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila and humans.

cell biology↗

bioRxiv2019

Intra-strain elicitation and suppression of plant immunity by Ralstonia solanacearum type-III effectors in Nicotiana benthamiana

Effector proteins delivered inside plant cells are powerful weapons for bacterial pathogens, but this exposes the pathogen to potential recognition by the plant immune system. Therefore, the effector repertoire of a given pathogen must be balanced for a successful infection. Ralstonia solanacearum is an aggressive pathogen with a large repertoire of secreted effectors. One of these effectors, RipE1, is conserved in most R. solanacearum strains sequenced to date. In this work, we found that RipE1 triggers immunity in N. benthamiana, which requires the immune regulator SGT1, but not EDS1 or NRCs. Interestingly, RipE1-triggered immunity induces the accumulation of salicylic acid (SA) and the overexpression of several genes encoding phenylalanine-ammonia lyases (PALs), suggesting that the unconventional PAL-mediated pathway is responsible for the observed SA biosynthesis. Surprisingly, RipE1 recognition also induces the expression of jasmonic acid (JA)-responsive genes and JA biosynthesis, suggesting that both SA and JA may act cooperatively in response to RipE1. Finally, we found that RipE1 expression leads to the accumulation of glutathione in plant cells, which precedes the activation of immune responses. R. solanacearum encodes another effector, RipAY, which is known to inhibit immune responses by degrading cellular glutathione. Accordingly, we show that RipAY inhibits RipE1-triggered immune responses. This work shows a strategy employed by R. solanacearum to counteract the perception of its effector proteins by the plant immune system.

plant biology↗

bioRxiv2019

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells (MSCs), the true identity of MSCs and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing single cell transcriptome analysis, we identified MSCs and delineated their bi-lineage differentiation paths in young, adult and aging mice. Among several newly discovered mesenchymal subpopulations, one is a distinct population of adipose-lineage cells that we named marrow environment regulating adipose cells (MERAs). MERAs are non-proliferative, post-progenitor cells that express many mature adipocyte markers but are devoid of lipid droplets. They are abundant in the bone marrow of young mice, acting as pericytes and stromal cells that form numerous connections among themselves and with other cells inside bone, including endothelial cells. Genetic ablation of MERAs disrupts marrow vessel structure, promotes de novo bone formation. Taken together, MERAs represent a unique population of adipose lineage cells that exist only in the bone marrow with critical roles in regulating bone and vessel homeostasis.

cell biology↗

bioRxiv2019

The loss of ATRX/DAXX complex disturbs rDNA heterochromatinization and promotes development of glioma

BackgroundRibosomal DNA (rDNA) transcription by the RNA polymerase I (Pol I) is a rate-limited step for ribosome synthesis, which is critical for cell growth, cell differentiation, and tumorigenesis. Meanwhile rDNA transcription is modulated by DNA methylation and histone epigenetic modification. Though with great progress in epigenetic research recently, it still remains much uncertain about the relationship of histone variant epigenetic modification and rDNA transcription.\n\nResultsIn this study, epigenetic profiles of silent rDNA in next-generation sequencing datasets were examined. We found that the chaperone of histone variant H3.3, the alpha-thalassemia/mental retardation X-linked syndrome protein (ATRX)/death domain-associated protein (DAXX) complex, and methyltransferase SET domain bifurcated 1 (Setdb1, also known as ESET) help maintain H3.3K9me3 modifications among the promoter and coding regions of silent rDNA. Our experiments further confirmed that DAXX depletion leads to the conversion of silent rDNA into upstream binding factor-bound active rDNA and the release of rDNA transcriptional potency. Support for this model is provided by data from a low-grade glioma in which ATRX is lost and a higher level of ribosomal biosynthesis, nucleolus activity, and proliferation are observed.\n\nConclusionsWe demonstrate a model of epigenetic regulation for rDNA with roles for the ATRX/DAXX complex and H3.3/H3K9me3 modifications identified. Thus, loss of ATRX/DAXX may represent a driving force for tumorigenesis due to its contribution to the release of rDNA transcriptional potency.

cancer biology↗