Biology subjects

Zhou, H.

Publications and source records attributed to Zhou, H..

At least 343 records · Page 19Linked to original sources

bioRxiv2021

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency

TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, whether and how TET1 exerts catalytic activity-independent functions in regulating bivalent genes is not well understood. Using a proteomics approach, we mapped the TET1 interactome in mouse ESCs and identified PSPC1 as a novel TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2) complex. We establish that PSPC1 and TET1 repress, and Neat1, the PSPC1 cognate lncRNA, activates the bivalent gene expression. In ESCs, Neat1 tethers the TET1-PSPC1 pair with PRC2 at bivalent promoters. During the ESC-to-formative epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 promote PRC2 chromatin occupancy at bivalent gene promoters while restricting Neat1 functions in facilitating PRC2 binding to bivalent gene transcripts. Our study uncovers a novel TET1-PSPC1-Neat1 molecular axis that modulates PRC2 binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency. In BriefTET1 is a transcriptional repressor for bivalent genes in pluripotent stem cells, but its mechanistic action on stem cell bivalency is unclear. Huang et al. use proteomics and genetic approaches to reveal that catalytic activity-independent functions of TET1, coordinated with the paraspeckle components PSPC1 and its cognate lncRNA Neat1, dynamically regulates stem cell bivalency by modulating PRC2 binding affinity to chromatin and bivalent gene transcripts in pluripotent state transition. HighlightsO_LIThe TET1 interactome identifies PSPC1 as a novel partner in ESCs C_LIO_LITET1 and PSPC1 repress bivalent genes by promoting PRC2 chromatin occupancy C_LIO_LINeat1 facilitates bivalent gene activation by promoting PRC2 binding to their mRNAs C_LIO_LINeat1 bridges the TET1-PSPC1 and PRC2 complexes in regulating bivalent gene transcription C_LI

developmental biology↗

bioRxiv2021

Protein-based RBD-C-tag COVID-19 Vaccination Candidate Elicits Protection Activity against SARS-COV-2 Variant Infection

The identification of a vaccination candidate against COVID-19 providing protecting activity against emerging SARS-COV-2 variants remains challenging. Here, we report protection activity against a spectrum of SARS-COV-2 and variants by immunization with protein-based recombinant RBD-C-tag administered with aluminum-phosphate adjuvant intramuscularly. Immunization of C57BL/6 mice with RBD-C-tag resulted in the in vivo production of IgG antibodies recognizing the immune-critical spike protein of the SARS-COV-2 virus as well as the SARS-COV-2 variants alpha ("United Kingdom"), beta ("South Africa"), gamma ("Brazil/Japan"), and delta ("India") as well as wt-spike protein. RBD-C-tag immunization led to a desired Th1 polarization of CD4 T cells producing IFN{gamma}. Importantly, RBD-C-tag immunization educated IgG production delivers antibodies that exert neutralizing activity against the highly transmissible SARS-COV-2 virus strains "Washington", "South Africa" (beta), and "India" (delta) as determined by conservative infection protection experiments in vitro. Hence, the protein-based recombinant RBD-C-tag is considered a promising vaccination candidate against COVID-19 and a broad range of emerging SARS-COV-2 virus variants.

microbiology↗

bioRxiv2021

AFA: Computationally efficient Ancestral Frequency estimation in Admixed populations: the Hispanic Community Health Study/Study of Latinos

We developed a computationally efficient method, Ancestral Frequency estimation in Admixed populations (AFA), to estimate the frequencies of bi-allelic variants in admixed populations with an unlimited number of ancestries. AFA uses maximum likelihood estimation by modeling the conditional probability of having an allele given proportions of genetic ancestries. It can be applied using either global or local proportions of genetic ancestries. Simulations mimicking admixture demonstrated the high accuracy of the method. We implemented the method on data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), an admixed population with three predominant continental ancestries: Amerindian, European, and African. Comparison of the European and African estimated frequencies to the respective gnomAD frequencies demonstrated high correlations, with Pearson R2=0.97-0.99. We provide a genome-wide dataset of the estimated three ancestral allele frequencies in HCHS/SOL for all available variants with allele frequency between 5%-95% in at least one of the three ancestral populations.

genomics↗

bioRxiv2021

Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock

Background and PurposeGpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with no established physiological function in vivo. The purpose of this study was to determine the role of Gpr19 in the circadian clock system. Experimental ApproachWe examined whether and how the master circadian clock neurons in the suprachiasmatic nucleus (SCN) express Gpr19. By analysing Gpr19-deficient (Gpr19-/-) mice, we asked whether Gpr19 has a role in modulating free-running period and light resetting capacity of the circadian clock. Key ResultsCompared with the known common core clock genes, Gpr19 was identified to show several distinct yet limited features related to the circadian clock. Gpr19 mRNA was mainly expressed in the middle-to-dorsal region of the SCN. A conserved cAMP-responsive element within the Gpr19 promoter drove the circadian expression of Gpr19. Gpr19-/- mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity in a 12-h light/12-h dark cycle. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. Gpr19-/- mice had a reduced capacity for phase shift to early subjective night light. The defect was only observed for phase-delay, but not phase-advance, and accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral part of the SCN, in Gpr19-/- mice. Conclusion and ImplicationsGpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and thus may be a potential target for alleviating circadian clock disorders. O_LIWhat is already known: Gpr19 is an evolutionarily conserved class-A orphan receptor with no established physiological role in vivo. The SCN is a light-entrainable master circadian pacemaker governing daily rhythms of behaviour and physiology. C_LIO_LIWhat this study adds: Gpr19 is an SCN-enriched orphan GPCR whose levels fluctuate in a circadian fashion. Gpr19 is a functional clock modulator involved in period determination and phase resetting. C_LIO_LIClinical significance: Targeting the orphan receptor Gpr19 may provide a therapeutic approach for alleviating circadian clock disorders. C_LI

neuroscience↗

bioRxiv2021

Multivariate Genomewide Association Analysis with IHT

1In genome-wide association studies (GWAS), analyzing multiple correlated traits is potentially superior to conducting multiple univariate analyses. Standard methods for multivariate GWAS operate marker-by-marker and are computationally intensive. We present a penalized regression algorithm for multivariate GWAS based on iterative hard thresholding (IHT) and implement it in a convenient Julia package MendelIHT.jl (https://github.com/OpenMendel/MendelIHT.jl). In simulation studies with up to 100 traits, IHT exhibits similar true positive rates, smaller false positive rates, and faster execution times than GEMMAs linear mixed models and mv-PLINKs canonical correlation analysis. On UK Biobank data, our IHT software completed a 3-trait joint analysis in 20 hours and an 18-trait joint analysis in 53 hours, requiring up to 80GB of computer memory. In short, our software enables geneticists to fit a single regression model that simultaneously considers the effect of all SNPs and dozens of traits.

genetics↗

bioRxiv2021

Ribosomal protein L23 drives the metastasis of hepatocellular carcinoma via upregulating MMP9

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally and tumor metastasis is one of the major causes of high mortality. To identify novel molecules contributing to HCC metastasis is critical to understanding the underlining mechanism of cancer metastasis. Here, combining the analyze based on published database and liver tissues from HCC patients, we identified that RNA binding protein L23 (RPL23) as a tumor metastasis driver in HCC. RPL23 was elevated in HCC and closely related to poor clinical outcomes. Furthermore, RPL23 depletion inhibited HCC cell proliferation, migration and invasion, while RPL23 overexpression promoted HCC cell metastasis. Mechanistically, RPL23 positively regulated MMP9 expression by stabilizing its mRNA. And increased MMP9 is involved in RPL23-mediated HCC metastasis. Importantly, RPL23 silencing reduced tumor growth and metastasis in vivo. In summary, we identified that RPL23 play an important role in HCC metastasis in an MMP9-dependent manner and may be a novel potential therapeutic target for HCC tumorigenesis and metastasis.

cancer biology↗

bioRxiv2021

The transcription factor Zeb2 drives differentiation of age-associated B cells

Age-associated B-cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screen for transcription factors driving ABC formation and find Zeb2 is required for human and mouse ABC differentiation in-vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B-cells. In mice with TLR7-driven lupus, Zeb2 is essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B-cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation requires Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduces ABC accumulation in autoimmune mice and patients. Zeb2 thus emerges as a driver of B-cell autoimmunity. One-Sentence SummaryZeb2 is essential for Age-associated B cells differentiation and function.

immunology↗

bioRxiv2021

Comparison of Neutralizing Antibody Titers Elicited by mRNA and Adenoviral Vector Vaccine against SARS-CoV-2 Variants

The increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine efficacy. Here, neutralizing antibody titers elicited by mRNA-based and an adenoviral vector-based vaccine against variant pseudotyped viruses were compared. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals were of low neutralizing titer (IC50 <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest the benefit of a second immunization following Ad26.COV2.S to increase protection against the variants.

immunology↗

bioRxiv2021

SARS-CoV-2 Lambda Variant Remains Susceptible to Neutralization by mRNA Vaccine-elicited Antibodies and Convalescent Serum

The SARS-CoV-2 lambda variant (lineage C.37) was designated by the World Health Organization as a variant of interest and is currently increasing in prevalence in South American and other countries. The lambda spike protein contains novel mutations within the receptor binding domain (L452Q and F490S) that may contribute to its increased transmissibility and could result in susceptibility to re-infection or a reduction in protection provided by current vaccines. In this study, the infectivity and susceptibility of viruses with the lambda variant spike protein to neutralization by convalescent sera and vaccine-elicited antibodies was tested. Virus with the lambda spike had higher infectivity and was neutralized by convalescent sera and vaccine-elicited antibodies with a relatively minor 2.3-3.3-fold decrease in titer on average. The virus was neutralized by the Regeneron therapeutic monoclonal antibody cocktail with no loss of titer. The results suggest that vaccines in current use will remain protective against the lambda variant and that monoclonal antibody therapy will remain effective.

immunology↗

bioRxiv2021

Rad52 mediates class-switch DNA recombination to IgD

While the biology of IgD begins to be better understood, the mechanism of expression of this phylogenetically old and highly conserved Ig remains unknown. In B cells, IgD is expressed together with IgM as transmembrane receptor for antigen through alternative splicing of long primary VHDJH-C-s-m-C{delta}-s-m RNAs, which also underpin secreted (s)IgD. IgD is also expressed through class switch DNA recombination (CSR), as initiated by AID-mediated double-strand DNA breaks (DSBs) in S and {sigma}{delta}, and resolution of such DSBs by a still unknown mechanism. This synapses S with {sigma}{delta} region DSB resected ends leading to insertion of extensive S-S junction microhomologies, unlike Ku70/Ku86-dependent NHEJ which resolves DSB blunt ends in CSR to IgG, IgA and IgE with little or no microhomologies. Our previous demonstration of a novel role of Rad52 in a Ku70/Ku86-independent "short-range" microhomology-mediated synapsis of intra-S region DSBs led us to hypothesize that this homologous recombination DNA annealing factor is also involved in short-range microhomology-mediated alternative endjoining (A-EJ) recombination of S with {sigma}{delta}. We found that induction of IgD CSR by selected stimuli downregulated Zfp318 (the suppressor of C-s-m transcription termination), promoted Rad52 phosphorylation and Rad52 recruitment to S and {sigma}{delta}, leading to S-{sigma}{delta} recombination with extensive microhomologies, VHDJH-C{delta}s transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52-/- B cells aborted IgD CSR in vitro and in vivo and dampened the specific IgD antibody response to OVA. Further, Rad52 knockdown in human B cells virtually abrogated IgD CSR. Finally, Rad52 phosphorylation was associated with high levels of IgD CSR and anti-nuclear IgD autoantibodies in lupus-prone mice and lupus patients. Thus, Rad52 effects CSR to IgD through microhomology-mediated A-EJ and in concert with Zfp318 modulation. This is a previously unrecognized, critical and dedicated role of Rad52 in mammalian DNA repair that provides a mechanistic underpinning to CSR A-EJ.

immunology↗

bioRxiv2021

The TR locus annotation and characteristics of Rhinolophus ferrumequinum

T cell antigen receptors (TCRs) in vertebrate could be divided into {beta} or {gamma}{delta}, which are encoded by TRA/D, TRG and TRB loci respectively. TCRs play a central role in mammal cellular immunity, which are functionally produced by rearrangement of V gene, D gene, J gene and C gene in the loci. Bat is the only mammal with flying ability, and is considered as the main host of zoonotic virus, which occupies an important position in the field of public health. At present, little is known about the composition of bat TRs gene. According to the whole genome sequencing results of the Rhinolophus ferrumequinum, and referring to the TR/IG annotation rules formulated by IMGT. We make a complete annotation on the TRA/D, TRG and TRB loci of the Rhinolophus ferrumequinum. A total of 128 V segments, 3 D segments, 85 J segments and 6 C segments were annotated, in addition to compared with the known mammalian, the characteristics of the TRs locus and germline genes of the Rhinolophus ferrumequinum were analyzed.

molecular biology↗

bioRxiv2021

Immunogenicity and In vivo protection of a variant nanoparticle vaccine that confers broad protection against emerging SARS-CoV-2 variants

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally. As SARS-CoV-2 has transmitted from person to person, variant viruses have emerged with elevated transmission rates and higher risk of infection for vaccinees. We present data showing that a recombinant prefusion-stabilized Spike (rS) protein based on the B.1.351 sequence (rS-B.1.351) was highly immunogenic in mice and produced neutralizing antibodies against SARS-CoV-2/WA1, B.1.1.7, and B.1.351. Mice vaccinated with our prototype vaccine NVX-CoV2373 (rS-WU1) or rS-B.1.351 alone, in combination, or as a heterologous prime boost, were protected when challenged with live SARS-CoV-2/B.1.1.7 or SARS-CoV-2/B.1.351. Virus titer was reduced to undetectable levels in the lungs post-challenge in all vaccinated mice, and Th1-skewed cellular responses were observed. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with NVX-CoV2373 (rS-WU1). An rS-B.1.351 vaccine alone or in combination with prototype rS-WU1 induced protective antibody- and cell-mediated responses that were protective against challenge with SARS-CoV-2 variant viruses.

immunology↗

bioRxiv2021

BSCL2/Seipin Deficiency in Heart Causes Energy Deficit and Heart Failure via Inducing Excessive Lipid Catabolism

Heart failure (HF) is one of the leading causes of death world-wide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2-/- mice exhibit hypertrophic cardiomyopathy. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Here we show that mice with cardiac-specific deletion of Bscl2 (Bscl2cKO) developed dilated HF. Myocardial BSCL2 deletion led to elevated ATGL expression and FA oxidation (FAO) along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, heart failure in Bscl2cKO mice could be partially reversed by pharmacological inhibition of FAO, or prevented by high fat diet (HFD) feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2cKO hearts, which were partially normalized by FAO inhibition or HFD. Our study reveals a new form of HF with excessive lipid catabolism, and identifies a crucial cardiomyocyte-specific role of BSCL2 in controlling cardiac lipid catabolism, energy state and contractile function. It also provides novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.

physiology↗

bioRxiv2021

Revealing the full biosphere structure and versatile metabolic functions in the deepest ocean sediment of the Challenger Deep

BackgroundThe full biosphere structure and functional exploration of the microbial communities of the Challenger Deep of the Mariana Trench, the deepest known hadal zone on Earth, lag far behind that of other marine realms. ResultsWe adopt a deep metagenomics approach to investigate the microbiome in the sediment of Challenger Deep, Mariana Trench. We construct 178 metagenome-assembled genomes (MAGs) representing 26 phyla, 16 of which are reported from hadal sediment for the first time. Based on the MAGs, we find the microbial community functions are marked by enrichment and prevalence of mixotrophy and facultative anaerobic metabolism. The microeukaryotic community is found to be dominated by six fungal groups that are characterized for the first time in hadal sediment to possess the assimilatory and dissimilatory nitrate/sulfate reduction, and hydrogen sulfide oxidation pathways. By metaviromic analysis, we reveal novel hadal Caudovirales clades, distinctive virus-host interactions, and specialized auxiliary metabolic genes for modulating hosts nitrogen/sulfur metabolism. The hadal microbiome is further investigated by large-scale cultivation that cataloged 1070 bacterial and 19 fungal isolates from the Challenger Deep sediment, many of which are found to be new species specialized in the hadal habitat. ConclusionOur hadal MAGs and isolates increase the diversity of the Challenger Deep sediment microbial genomes and isolates present in the public. The deep metagenomics approach fills the knowledge gaps in structure and diversity of the hadal microbiome, and provides novel insight into the ecology and metabolism of eukaryotic and viral components in the deepest biosphere on earth.

microbiology↗

bioRxiv2021

The Spike Proteins of SARS-CoV-2 B.1.617 and B.1.618 Variants Identified in India Provide Partial Resistance to Vaccine-elicited and Therapeutic Monoclonal Antibodies.

Highly transmissible SARS-CoV-2 variants recently identified in India designated B.1.617 and B.1.618 have mutations within the spike protein that may contribute to their increased transmissibility and that could potentially result in re-infection or resistance to vaccine-elicited antibody. B.1.617 encodes a spike protein with mutations L452R, E484Q, D614G and P681R while the B.1.618 spike has mutations {Delta}145-146, E484K and D614G. We generated lentiviruses pseudotyped by the variant proteins and determined their resistance to neutralization by convalescent sera, vaccine-elicited antibodies and therapeutic monoclonal antibodies. Viruses with B.1.617 and B.1.618 spike were neutralized with a 2-5-fold decrease in titer by convalescent sera and vaccine-elicited antibodies. The E484Q and E484K versions were neutralized with a 2-4-fold decrease in titer. Virus with the B.1.617 spike protein was neutralized with a 4.7-fold decrease in titer by the Regeneron monoclonal antibody cocktail as a result of the L452R mutation. The modest neutralization resistance of the variant spike proteins to vaccine elicited antibody suggests that current vaccines will remain protective against the B.1.617 and B.1.618 variants.

immunology↗

bioRxiv2021

SmProt: a reliable repository with comprehensive annotation of small proteins identified from ribosome profiling

Small proteins specifically refer to proteins consisting of less than 100 amino acids translated from small open reading frames (sORFs), which were usually missed in previous genome annotation. The significance of small proteins has been revealed in current years, along with the discovery of their diverse functions. However, systematic annotation of small proteins is still insufficient. SmProt was specially developed to provide valuable information on small proteins for scientific community. Here we present the update of SmProt, which emphasizes reliability of translated sORFs, genetic variants in translated sORFs, disease-specific sORFs translation events or sequences, and significantly increased data volume. More components such as non-AUG translation initiation, function, and new sources are also included. SmProt incorporated 638,958 unique small proteins curated from 3,165,229 primary records, which were computationally predicted from 419 ribosome profiling (Ribo-seq) datasets and collected from the literature and other sources originating from 370 cell lines or tissues in 8 species (Homo sapiens, Mus musculus, Rattus norvegicus, Drosophila melanogaster, Danio rerio, Saccharomyces cerevisiae, Caenorhabditis elegans, and Escherichia coli). In addition, small protein families identified from human microbiomes were collected. All datasets in SmProt are free to access, and available for browse, search, and bulk downloads at http://bigdata.ibp.ac.cn/SmProt/.

bioinformatics↗

bioRxiv2021

Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China

Persistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 358 viral genomes of four major HPV types, including HPV 16 (n=82), 18 (n=35), 52 (n=121) and 58 (n=100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 strains associated with potentially high oncogenicity. These findings expanded our knowledge on the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.

genomics↗

bioRxiv2021

In situ electro-sequencing in three-dimensional tissues

Pairwise mapping of single-cell gene expression and electrophysiology in intact three-dimensional (3D) tissues is crucial for studying electrogenic organs (e.g., brain and heart)1-5. Here, we introduce in situ electro-sequencing (electro-seq), combining soft bioelectronics with in situ RNA sequencing to stably map millisecond-timescale cellular electrophysiology and simultaneously profile a large number of genes at single-cell level across 3D tissues. We applied in situ electro-seq to 3D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches, precisely registering the CM gene expression with electrophysiology at single-cell level, enabling multimodal in situ analysis. Such multimodal data integration substantially improved the dissection of cell types and the reconstruction of developmental trajectory from spatially heterogeneous tissues. Using machine learning (ML)-based cross-modal analysis, in situ electro-seq identified the gene-to-electrophysiology relationship over the time course of cardiac maturation. Further leveraging such a relationship to train a coupled autoencoder, we demonstrated the prediction of single-cell gene expression profile evolution using long-term electrical measurement from the same cardiac patch or 3D millimeter-scale cardiac organoids. As exemplified by cardiac tissue maturation, in situ electro-seq will be broadly applicable to create spatiotemporal multimodal maps and predictive models in electrogenic organs, allowing discovery of cell types and gene programs responsible for electrophysiological function and dysfunction.

genomics↗