Biology subjects

Quan, H.

Publications and source records attributed to Quan, H..

10 recordsLinked to original sources

bioRxiv2024

Multi-step engineered adeno-associated virus enables whole-brain mRNA delivery

Adeno-associated viruses (AAVs) are commonly used vectors for DNA delivery in gene therapy. Here we developed a system that enables the AAV shell to package mRNAs by multi-step introduction of RNA-packaging components and modification of AAV Rep proteins. The resultant mRNA-carrying AAVs (RAAVs) retained most properties of conventional AAVs, including capsid composition, virus morphology, and tissue tropism. These RAAVs could mediate mRNA transfer into target cells and tissues, leading to transient expression of the functional protein. Importantly, intravenously injected RAAVs efficiently crossed the blood-brain barrier (BBB) and infected the whole mouse brain. Thus, the DNA viral vector could be modified for RNA delivery, and our RAAV represents the first highly efficient BBB-crossing mRNA delivery system that could be used for therapeutic purposes via whole-brain infection.

bioengineering↗

bioRxiv2022

Characterization of network hierarchy reflects cell-state specificity in genome organization

Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C datasets and derived the chromatin contact networks (CCNs). We discovered significant decreases in information transmission efficiencies in CCNs of colorectal cancer (CRC) and T-lineage acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Through network embedding in Poincare disk, the hierarchy depths of CCNs from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of CCN change was observed for the transition from embryo to differentiated primary tissues. During early embryo developments of both human and mouse, the hierarchy of embedded chromatin structure gradually establishes. Additionally, we found tissue-specific conservation of hierarchy order in normal CCNs, which was disturbed in tumor. Our findings uncover the cell-state related hierarchical characteristics in chromatin structure, which reveal chromatin loci that play important roles in stabilizing the cellular conditions.

bioinformatics↗

bioRxiv2021

Liposomal Dexamethasone Reduces A/H1N1 Influenza-Associated Morbidity in Mice

Re-emerging viral threats have continued to challenge the medical and public health systems. It has become clear that a significant number of severe viral infection cases are due to an overreaction of the immune system, which leads to hyperinflammation. In this study, we aimed to demonstrate the therapeutic efficacy of the dexamethasone nanomedicine in controlling the symptoms of influenza infection. We found that the A/Wisconsin/WSLH34939/2009 (H1N1) infection induced severe pneumonia in mice with a death rate of 80%, accompanied by significant epithelial cell damage, infiltration of immune cells, and accumulation of pro-inflammatory cytokines in the airway space. Moreover, the intranasal delivery of liposomal dexamethasone during disease progression reduced the death rate by 20%. It also significantly reduced the protein level of tumor necrosis factor-alpha (TNF), interleukin1{beta} (IL-1{beta}), IL-6, and the C-X-C motif chemokine ligand 2 (CXCL2) as well as the number of infiltrated immune cells in the bronchoalveolar lavage fluids as compared to the free drug. It was found that the liposomal dexamethasone was mainly distributed into the monocyte/macrophages in the lungs, suggesting its mode of action via the specific delivery of the drug into myeloid cells as a major cell population for inducing the cytokine storm. Taken together, the intranasal delivery of liposomal dexamethasone may serve as a novel promising therapeutic strategy for the treatment of influenza A-induced pneumonia. ImportanceInfluenza A virus causes annual epidemics and sporadic pandemics of respiratory diseases. An excessive immune response, called a cytokine storm, caused by the influenza virus is the most common complication of influenza infection that is associated with high levels of morbidity and mortality. Here, we report that the liposomal dexamethasone targeting the monocytes/macrophages during disease progression reduced the death rate as well as the protein level of inflammatory cytokines and the number of immune cells. Therefore, the findings of this study may be applied to address the limitations of the current strategies for the treatment of influenza.

immunology↗

bioRxiv2021

Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes

The author has withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2019/521401. Therefore, the author does not wish this work to be cited as a reference for the project. Please cite and refer to the preprint BIORXIV/2019/521401 if necessary. If you have any questions, please contact the corresponding author (gaoyq@pku.edu.cn).

developmental biology↗

bioRxiv2020

Genome Wide Analysis of Dinucleotide Distribution along the Genomes of Species and its Biological Implication

Dinucleotide densities and their distribution patterns vary significantly among species. Previous studies revealed that CpG is susceptible to methylation, enriched at topologically associating domains (TADs) boundaries and its distribution along the genome correlates with chromatin compartmentalization. However, the multi-scale organizations of CpG in the linear genome, their role in chromatin organization, and how they change along the evolution are only partially understood. By comparing the CpG distribution at different genomic length scales, we quantify the difference between the CpG distributions of different species and evaluate how the hierarchical uneven CpG distribution appears in evolution. The clustering of species based on the CpG distribution is consistent with the phylogenetic tree. Interestingly, we found the CpG distribution and chromatin structure to be correlated in many different length scales, especially for mammals and avians, consistent with the mosaic CpG distribution in the genomes of these species.

evolutionary biology↗

bioRxiv2020

Toward an understanding of the relation between gene regulation and 3D genome organization

The development and usage of chromosome conformation capture technologies have provided great details on 3D genome organization and provide great opportunities to understand how gene regulation is affected by the 3D chromatin structure. Previously, we identified two types of sequence domains, CGI forest and CGI prairie, which tend to segregate spatially, but to different extent in different tissues/cell states. To further quantify the association of domain segregation with gene regulation and differentiation, we analyzed in this study the distribution of genes of different tissue specificities along the linear genome, and found that the distribution patterns are distinctly different in forests and prairies. The tissue-specific genes (TSGs) are significantly enriched in the latter but not in the former and genes of similar expression profiles among different cell types (co-activation/repression) also tend to cluster in specific prairies. We then analyzed the correlation between gene expression and the spatial contact revealed in Hi-C measurement. Tissue-specific forest-prairie contact formation was found to correlate with the regulation of the TSGs, in particular those in the prairie domains, pointing to the important role gene positioning, in the linear DNA sequence as well as in 3D chromatin structure, plays in gene regulatory network formation.

genetics↗

bioRxiv2020

Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis

The three-dimensional (3D) chromatin structure, together with DNA methylation and other epigenetic marks, profoundly affects gene expression and displays abnormal behaviors in cancer cells. We elucidated the chromatin architecture remodeling in carcinogenesis from the perspective of spatial interactions between CGI forest and prairie domains, which are two types of megabase-sized domains defined by different sequence features but show distinct epigenetic and transcriptional patterns. DNA sequence strongly affects chromosome spatial interaction, DNA methylation and gene expression. Globally, forests and prairies show enhanced spatial segregation in cancer cells and such structural changes are accordant with the alteration of CGI interactions and domain boundary insulation, which could affect vital cancer-related properties. As the cancer progresses, a gradual increase of the DNA methylation difference between the two types of DNA domains is also observed for many different types of cancers. These observations are consistent with the change of transcriptional level differences of genes in these two domains, suggesting a highly-connected global structural, epigenetic and transcriptional activity changes in carcinogenesis.

cancer biology↗

bioRxiv2019

Phase separation during mouse early embryonic development and underlying genetic and epigenetic correlations

Chromatin undergoes drastic structural organization and epigenetic reprogramming during embryonic development. We present here a consistent view of the chromatin structural change, epigenetic reprogramming and the corresponding sequence dependence in both mouse and human embryo development. The two types of domains, identified earlier as forests and prairies, become spatially segregated during embryonic development, with the exception of zygotic genome activation (ZGA) and implantation, at which notable domain mixing occurs. Structural segregation largely coincides with DNA methylation and gene expression changes. Genes located in mixed prairie domains show proliferation and ectoderm differentiation-related function in ZGA and implantation, respectively. Chromatin of ectoderm shows the weakest and endoderm the strongest domain segregation in germ layers. This chromatin structure difference between different germ layers generally enlarges in further differentiation. The systematic chromatin structure establishment and its sequence-based segregation strongly suggest DNA sequence as a possible driving force for the establishment of chromatin 3D structures which affect profoundly the expression profile. Other possible factors correlated with/influencing chromatin structures, including temperature, germ layers, and cell cycle, were discussed for an understanding of concerted chromatin structure and epigenetic changes in development.

developmental biology↗

bioRxiv2018

Transcriptomic and functional analysis of the oosome, a unique form of germplasm in the wasp Nasonia vitripennis

BackgroundThe oosome is the germline determinant in the wasp Nasonia vitripennis and is homologous to the polar granules of Drosophila. Despite a common evolutionary origin and developmental role, the oosome is morphologically quite distinct from polar granules. It is a solid sphere that migrates within the cytoplasm before budding out and forming pole cells.\n\nResultsTo gain an understanding of both the molecular basis of the novel form of the oosome, and the conserved essential features of germ plasm, we quantified and compared transcript levels between embryo fragments that contained the oosome, and those that did not. The identity of the localized transcripts indicated that Nasonia uses different molecules to carry out conserved germ plasm functions. In addition, functional testing of a sample of localized transcripts revealed potentially novel mechanisms of ribonucleoprotein assembly and pole cell cellularization in the wasp.\n\nConclusionsOur results demonstrate that numerous novel and unexpected molecules have been recruited in order produce the unique characteristics of the oosome and pole cell formation in Nasonia. This work will serve as the basis for further investigation into the patterns of germline determinant evolution among insects, the molecular basis of extreme morphology of ribonucleoproteins, and the incorporation of novel components into developmental networks.

developmental biology↗

bioRxiv2018

From 1D sequence to 3D chromatin dynamics and cellular functions: a phase separation perspective

The high-order chromatin structure plays a non-negligible role in gene regulation. However, the mechanism for the formation of different chromatin structures in different cells and the sequence dependence of this process remain to be elucidated. As the nucleotide distributions in human and mouse genomes are highly uneven, we identified CGI forest and prairie genomic domains based on CGI density, which better segregates genomic elements along the genome than GC content. The genome is then divided into two sequentially, epigenetically, and transcriptionally distinct regions. These two types of megabase-sized domains spatially segregate, but to a different extent in different cell types. Overall, the forests and prairies gradually segregate from each other in development, differentiation, and senescence. The multi-scale forest-prairie spatial intermingling is cell-type specific and increases in differentiation, thus helps define the cell identity. We propose that the phase separation of the 1D mosaic sequence in space, serving as a potential driving force, together with cell type specific epigenetic marks and transcription factors, shapes the chromatin structure in different cell types and renders them distinct genomic properties. The mosaicity of the genome manifested in terms of alternative forests and prairies of a species could be related to its biological processes such as differentiation, aging and body temperature control.

biophysics↗