Biology subjects

Yuan, S.

Publications and source records attributed to Yuan, S..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

A Positive Regulatory Feedback Loop Between 1 EKLF/ KLF1 and TAL1/SCL2 Sustaining the Erythropoiesis

The erythroid Kruppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf-/-) mouse embryos, we have identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with molecular/cellular analysis of mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tall gene promoter in combination with in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates Tall gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors that sustains the mammalian erythropoiesis.

cell biology↗

bioRxiv2021

Multiomics Interrogation into HBV (Hepatitis B Virus)-Host Interaction Reveals Novel Coding potential in Human Genome, and Identifies Canonical and Non-canonical Proteins as Host Restriction Factors against HBV

Hepatitis B Virus constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing are conducted on a recently established HBV replication system. We have identified multiomic DEGs (differentially expressed genes) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical ORFs including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown SIRT6 had opposite effect. Furthermore, the expression of SIRT6 was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infection in vitro and in vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.

microbiology↗

bioRxiv2021

Cyto/myeloarchitectural changes of cortical gray matter and superficial white matter in early neurodevelopment: Multimodal MRI study of preterm neonates

The developing cerebral cortex undergoes rapid microstructural and morphological changes throughout the third trimester. Recently, increased attention has been focused on the identification of imaging features that represent the underlying cortical cyto/myeloarchitecture driving intracortical myelination and the maturation of cortical gray matter (GM) and its adjacent superficial white matter (sWM). However, the characterization and spatiotemporal pattern of complex cyto/myeloarchitectural changes in this critical time period remain incompletely understood. Using 92 MRI scans from 78 preterm neonates (baseline: n{square}={square}78, postmenstrual age=33.1{+/-}1.8 weeks; follow-up: n=14, 37.3{+/-}1.3), the current study leveraged combined T1/T2 intensity ratio and diffusion tensor imaging (DTI) measurements, including fractional anisotropy (FA) and mean diffusivity (MD), to characterize the cyto/myeloarchitectural architecture of cortical GM and its adjacent sWM in preterm neonates. DTI metrics during these weeks showed an overall linear developmental trajectory: FA decreased along with time in GM but increased in sWM; MD decreased in both GM and sWM. In contrast, T1/T2 measurements showed a distinctive parabolic developmental trajectory, revealing additional cyto/myeloarchitectural signature inferred. Furthermore, the spatiotemporal courses of T1/T2 ratio and DTI parameters were found to be regionally heterogeneous across the cerebral cortex, suggesting these imaging features specific relationship to regional cyto/myeloarchitectural maturation: faster T1/T2 ratio changes were found in the central, ventral, and temporal regions of GM and sWM, faster FA increases in anterior sWM areas, and faster MD decreases in GM and sWM central and cingulate areas. Taken together, our results may offer an explanation of the novel pattern of cyto/myeloarchitectural processes observed throughout the third trimester, including dendritic arborization, synaptogenesis, glial proliferation, as well as radial glial cell organization and apoptosis. Finally, T1/T2 ratio and DTI measurements were significantly associated with 1 year outcome scores of language and cognitive performance as well as perinatal clinical conditions, including intraventricular hemorrhage and chronic lung disease, demonstrating their potential as imaging biomarkers characterizing microstructural deviation in atypical neurodevelopment. Ultimately, with combined properties of cortical T1/T2 and DTI measurements, this study provides unique insights into the cellular processes and associated developmental mechanisms during the critical development of the third trimester.

neuroscience↗

bioRxiv2021

RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

RationaleThe identification of novel cardiomyocyte-intrinsic factors that support heart function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. ObjectiveTo identify and characterize conserved regulators of cardiomyocyte function. Methods and ResultsWe report that the RNA-binding protein RBPMS2 is required for myofibril organization and the regulation of intracellular calcium dynamics in both zebrafish embryos and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A differential expression screen in zebrafish uncovered enrichment of rbpms2 paralogs, rbpms2a and rbpms2b, in the myocardium. Double knock-out (rbpms2-null) embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Whole transcriptome sequencing and validation studies revealed differential alternative splicing of several genes linked to cardiomyopathies in humans, including myosin binding protein C3 (mybpc3) and phospholamban (pln), consistent with a role in causing the observed ventricular deficiencies. Further, RBPMS2-null hiPSC-CMs exhibit myofibril and calcium handling defects that are highly analogous to those observed in the rbpms2-null zebrafish ventricle. ConclusionsTaken together, our data identify RBPMS2 as a conserved and essential regulator of alternative splicing that is required for myofibrillar organization and optimal calcium handling from zebrafish to humans.

developmental biology↗

bioRxiv2021

Robust T1 MRI cortical surface pipeline for neonatal brain and systematic evaluation using multi-site MRI datasets

The human brain grows the most dramatically during the perinatal and early postnatal periods, during which preterm birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal MRI pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the CSF/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 preterm and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532{+/-}0.035mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with postmenstrual age (PMA) at scan (p<0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3mm at 28 weeks of PMA to 1.8mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.

bioinformatics↗

bioRxiv2020

Hippocampal Asymmetry of Regional Development and Structural Covariance in Preterm Neonates

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, the putative role of hippocampus dysfunction remains poorly understood in preterm neonates. Particularly, hemispherical asymmetry of the hippocampus has been well-noted, either structurally or functionally. How the preterm birth impairs the hippocampal development, and to what extent the hippocampus was impaired by preterm birth asymmetrical has not been well studied. In this study, we compared regional and local hippocampal development in term born neonates (n=361) and prematurely born infants at term-born equivalent age on MRI studies (n = 53) using T2 MRI images collected from the Developing Human Connectome Project (dHCP); We compared 1) volumetric growth; 2) shape development in the hippocampal hemispheres using Laplace-Beltrami eigen-projection and boundary deformation between the two groups; and 3) structural covariance between hippocampal vertices and the cortical thickness in cerebral cortex regions. We demonstrated that premature infants have smaller volume for the right hippocampi, while no difference was observed for the left hippocampi. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared to full-term peers, while an accelerated hippocampal thickness growth rate was found in left hippocampus only. Structural covariance analysis demonstrated that in premature infants, the structural covariance between hippocampi and limbic lobe were severely impaired compared to healthy term neonates only in left hemisphere. These data suggest that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure, with high degree of asymmetry. These findings suggested that the hippocampus shows high degree of vulnerability, particularly asymmetrical vulnerability or plasticity, in preterm neonates at the term-born equivalent age compared to full-term healthy controls.

neuroscience↗

bioRxiv2020

Sucrose represses the expression of the strigolactone signalling gene D3/RMS4/MAX2 to promote tillering

- Shoot branching, a major component of shoot architecture, is regulated by multiple signals. Previous studies have indicated that sucrose may promote branching through suppressing the inhibitory effect of the hormone strigolactone (SL). However, the molecular mechanisms underlying this effect are unknown. - Here we used molecular and genetic tools to identify the molecular targets underlying the antagonistic interaction between sucrose and SL. - We showed that sucrose antagonises the suppressive action of SL on tillering in rice and on the degradation of D53, a major target of SL signalling. Sucrose inhibits the expression of D3, the orthologue of the arabidopsis F-box protein MAX2 required for SL signalling. Over-expression of D3 prevents sucrose from inhibiting D53 degradation and enabled the SL inhibition of tillering under high sucrose. Sucrose also prevents SL-induced degradation of D14, the SL receptor involved in D53 degradation. Interestingly, D14 over-expression enhances D53 protein levels and sucrose-induced tillering. - Our results show that sucrose inhibits SL perception by targeting key components of SL signalling and, together with previous studies reporting the inhibition of SL synthesis by nitrate and phosphate, demonstrate the central role played by strigolactones in the regulation of plant architecture by nutrients.

plant biology↗

bioRxiv2020

Human Identical Sequences of SARS-CoV-2 Promote Clinical Progression of COVID-19 by Upregulating Hyaluronan via NamiRNA-Enhancer Network

The COVID-19 pandemic is a widespread and deadly public health crisis. The pathogen SARS-CoV-2 replicates in the lower respiratory tract and causes fatal pneumonia. Although tremendous efforts have been put into investigating the pathogeny of SARS-CoV-2, the underlying mechanism of how SARS-CoV-2 interacts with its host is largely unexplored. Here, by comparing the genomic sequences of SARS-CoV-2 and human, we identified five fully conserved elements in SARS-CoV-2 genome, which were termed as "human identical sequences (HIS)". HIS are also recognized in both SARS-CoV and MERS-CoV genome. Meanwhile, HIS-SARS-CoV-2 are highly conserved in the primate. Mechanically, HIS-SARS-CoV-2, behaving as virus-derived miRNAs, directly target to the human genomic loci and further interact with host enhancers to activate the expression of adjacent and distant genes, including cytokines gene and angiotensin converting enzyme II (ACE2), a well-known cell entry receptor of SARS-CoV-2, and hyaluronan synthase 2 (HAS2), which further increases hyaluronan formation. Noteworthily, hyaluronan level in plasma of COVID-19 patients is tightly correlated with severity and high risk for acute respiratory distress syndrome (ARDS) and may act as a predictor for the progression of COVID-19. HIS antagomirs, which downregulate hyaluronan level effectively, and 4-Methylumbelliferone (MU), an inhibitor of hyaluronan synthesis, are potential drugs to relieve the ARDS related ground-glass pattern in lung for COVID-19 treatment. Our results revealed that unprecedented HIS elements of SARS-CoV-2 contribute to the cytokine storm and ARDS in COVID-19 patients. Thus, blocking HIS-involved activating processes or hyaluronan synthesis directly by 4-MU may be effective strategies to alleviate COVID-19 progression.

molecular biology↗

bioRxiv2020

Maternal transmission of a paramutant phenotype requires intact DNMT2 functions in the male germline

INTRODUCTION Abstract INTRODUCTION Results DISCUSSION METHODS AND MATERIALS SUPPLEMENTARY MATERIALS Funding Author contributions Competing interests Data and materials availability Supplemental Figures REFERENCES DNA methylation, as a major epigenetic modification in the genome of higher eukaryotes, is catalyzed by DNA methyltransferase enzymes (DNMTs) by addition of a methyl group to the 5th carbon position of cytosine, resulting 5-methylcytosine (5mC) (1, 2). DNMT1 is the most abundant DNA methyltransferase in mammalian cells, and mainly methylate hemi-methylated CpG dinucleotides as a maintenance methyltransferase, although DNMT1 has also been ...

genetics↗

bioRxiv2020

mTOR S-nitrosylation inhibits autophagy and lysosomal proteolysis

Mammalian Target of Rapamycin (mTOR) is a master regulator of autophagy and lysosomes, and its downstream kinase-dependent pathways have been extensively characterized. Here, we report an unexpected kinase-independent regulation of autophagy and lysosomes by S-nitrosylation at Cys423 position of mTOR that resulted in suppression of VPS34 and PIKfyve-dependent phosphoinositide synthesis. Physiologically, S-nitrosylation of mTOR reduced basal lysosomal proteolysis via nitric oxide synthase (NOS)-mediated synthesis of NO from lysosomal arginine precursor, a marker of cellular nutrition status. Significantly, we found increased lysosomal NOS-mTOR complexes in APP-PS1 Alzheimers disease (AD) murine model, and increased mTOR S-nitrosylation in AD patient-derived fibroblasts. Lastly, we demonstrated that pharmacological inhibition of NOS or overexpression of mTORCys423Ala mutant reversed lysosomal and autophagic dysfunction in AD patient-derived fibroblasts, suggesting novel therapeutic strategies for autophagosome-lysosomal activation.

cell biology↗

bioRxiv2020

A DNA-origami nuclear pore mimic reveals nuclear entry mechanisms of HIV-1 capsid

The capsid of human immunodeficiency virus 1 (HIV-1) plays a pivotal role in viral nuclear import, but the mechanism by which the viral core passages the nuclear pore complex (NPC) is poorly understood. Here, we use DNA-origami mimics of the NPC, termed NuPODs (NucleoPorins Organized by DNA), to reveal the mechanistic underpinnings of HIV-1 capsid nuclear entry. We found that trimeric interface formed via three capsid protein hexamers is targeted by a triple-arginine (RRR) motif but not the canonical phenylalanine-glycine (FG) motif of NUP153. As NUP153 is located on the nuclear face of the NPC, this result implies that the assembled capsid must cross the NPC in vivo. This hypothesis is corroborated by our observations of tubular capsid assemblies penetrating through NUP153 NuPODs. NUP153 prefers to bind highly curved capsid assemblies including those found at the tips of viral cores, thereby facilitating capsid insertion into the NPC. Furthermore, a balance of capsid stabilization by NUP153 and deformation by CPSF6, along with other cellular factors, may allow for the intact capsid to pass NPCs of various sizes. The NuPOD system serves as a unique tool for unraveling the previously elusive mechanisms of nuclear import of HIV-1 and other viruses.

microbiology↗

bioRxiv2020

Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA.

The COVID-19 pandemic affects millions of people worldwide with a rising death toll. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its nonstructural protein 1 (Nsp1) to redirect host translation machinery to the viral RNA by binding to the ribosome and suppressing cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the transcriptome in human cells. The changes include repression of major gene clusters in ribosomal RNA processing, translation, mitochondria function, cell cycle and antigen presentation; and induction of factors in transcriptional regulation. We further gained a mechanistic understanding of the Nsp1 function by determining the cryo-EM structure of the Nsp1-40S ribosomal subunit complex, which shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the cryo-EM structure of the 48S preinitiation complex (PIC) formed by Nsp1, 40S, and the cricket paralysis virus (CrPV) internal ribosome entry site (IRES) RNA, which shows that this 48S PIC is nonfunctional due to the incorrect position of the 3 region of the mRNA. Results presented here elucidate the mechanism of host translation inhibition by SARS-CoV-2, provide insight into viral protein synthesis, and furnish a comprehensive understanding of the impacts from one of the most potent pathogenicity factors of SARS-CoV-2. HighlightsORF screen identified Nsp1 as a major cellular pathogenicity factor of SARS-CoV-2 Nsp1 broadly alters the gene expression programs in human cells Nsp1 inhibits translation by blocking mRNA entry channel Nsp1 prevents physiological conformation of the 48S PIC

molecular biology↗

bioRxiv2020

Repopulating Kupffer Cells Originate Directly from Hematopoietic Stem Cells

Kupffer cells (KCs) originate from yolk sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at stead state, and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adult remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided strong in vivo fate-mapping evidences that repopulating KCs originate directly from Hematopoietic stem cells not from preexisting KCs or from MOs. SignificanceThere is a standing controversy in the field regarding the cellular origin of repopulating macrophages. This paper provides strong in vivo fate-mapping evidences that repopulating KCs originate directly from hematopoietic stem cells not from preexisting KCs or from MOs, which presenting a completely novel understanding of the cellular origin of repopulating Kupffer Cells and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

cell biology↗

bioRxiv2020

Efficiency of a Randomized Confirmatory Basket Trial Design Constrained to Control the False Positive Rate by Indication

PURPOSEMolecular oncology determines biomarker-defined niche indications. Basket trials pool histologic indications sharing molecular pathophysiology, potentially improving development efficiency. Currently basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since false positive control by indications (FWER) may sometimes be required, we now simulate a variant of this basket design controlling FWER at 0.025k, the total FWER of k separate randomized trials. METHODSThe previous design eliminated indications at an interim analysis, conducting a final pooled analysis of remaining indications. To control FWER, we rechecked individual indications at a prospectively defined level of statistical significance after any positive pooled result. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling FWER and minimizing estimation bias were allowable. RESULTSSequential analyses (interim, pooled, and post-individual tests)) result in cumulative power losses. Optimal performance results when k = 3,4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power ("uncorrected") or at the power achieved in the basket trial ("corrected", because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible, with power {approx} 60%. CONCLUSIONSEven under FWER control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical. The design is particularly attractive when enrollment challenges preclude full powering of individual indications.

cancer biology↗

bioRxiv2020

High-Fiber Diet Restores Maternal Obesity-Induced Cognitive and Social Behavioral Deficits in Offspring via Regulating Gut Microbiota-Metabolites-Brain Axis

Maternal obesity has been reported to be related to the neurodevelopmental disorders in offspring. However, the underlying mechanisms and effective interventions remain unclear. Here, a cross-sectional study on 778 children aged 7-14 years in two cities of China indicates that the maternal obesity is highly associated with the poorer cognition and sociality of their children. Moreover, we also find that the maternal obesity in mice disrupts the behavior and the gut microbiome in the offspring, which are alleviated by a high-fiber diet in either dams or offspring. Co-housing and feces microbiota transplantation experiments reveal a causal relationship between the reshaped microbiota and the behavioral changes. Moreover, treatment of the microbiota-derived short-chain fatty acids exhibits a similar beneficial effect on alleviating the behavioral deficits in offspring. Together, our study purports the microbiota-metabolites-brain axis as a mechanism, and high-dietary fiber intake is a promising intervention against maternal obesity-induced cognitive and social dysfunctions.

neuroscience↗

bioRxiv2020

Human IgG cell neutralizing monoclonal antibodies block SARS-CoV-2 infection

The coronavirus induced disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a worldwide threat to human lives, and neutralizing antibodies present a great therapeutic potential in curing affected patients. We purified more than one thousand memory B cells specific to SARS-CoV-2 S1 or RBD (receptor binding domain) antigens from 11 convalescent COVID-19 patients, and a total of 729 naturally paired heavy and light chain fragments were obtained by single B cell cloning technology. Among these, 178 recombinant monoclonal antibodies were tested positive for antigen binding, and the top 13 binders with Kd below 0.5 nM are all RBD binders. Importantly, all these 13 antibodies could block pseudoviral entry into HEK293T cells overexpressing ACE2, with the best ones showing IC50s around 2-3 nM. We further identified 8 neutralizing antibodies against authentic virus with IC50s within 10 nM. Among these, 414-1 blocked authentic viral entry at IC50 of 1.75 nM and in combination with 105-38 could achieve IC50 as low as 0.45 nM. Meanwhile, we also found that 3 antibodies could cross-react with the SARS-CoV spike protein. Altogether, our study provided a panel of potent human neutralizing antibodies for COVID19 as therapeutics candidates for further development.

immunology↗

bioRxiv2020

Comprehensive mapping of the human cytokine gene regulatory network

Proper cytokine gene expression is essential in development, homeostasis, and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we use enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1,380 interactions between 265 TFs and 108 cytokine gene promoters, greatly expanding the known repertoire of TF-cytokine gene interactions. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that synergistically modulate cytokine gene expression, and to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.

immunology↗

bioRxiv2020

ZBTB18 interacts with CTBP2 and represses SREBP genes to inhibit fatty acid synthesis in glioblastoma

Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulate the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. Our study points at CTBP1/2 and LSD1 as co-activators of SREBP genes whose complex functional activity is altered by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 demethylase activity of H3 active marks leading to increased di-methylation of lysine 4 (H3K4me2). Concomitantly, we observed increased di-methylation of lysine 9 (H3K9me2), and decrease of the active mark H3K4me3 with consequent repression of the SREBP genes. In line with our findings, lipidomic analysis shows a reduction of several phospholipid species upon ZBTB18 expression. Our results outline a new epigenetic mechanism enrolled by ZBTB18 and its cofactors to regulate fatty acid synthesis that could be targeted to treat glioblastoma patients.

cancer biology↗