Biology subjects

Lei, J.

Publications and source records attributed to Lei, J..

7 recordsLinked to original sources

bioRxiv2018

Cell-type switches induced by stochastic histone modification inheritance

AO_SCPCAPBSTRACTC_SCPCAPCell plasticity is important for tissue developments during which somatic cells may switch between distinct states. Genetic networks to yield multistable states are usually required to yield multiple states, and either external stimuli or noise in gene expressions are trigger signals to induce cell-type switches between the states. In many biological systems, cells show highly plasticity and can switch between different state spontaneously, but maintaining the dynamic equilibrium of the cell population. Here, we considered a mechanism of spontaneous cell-type switches through the combination between gene regulation network and stochastic epigenetic state transitions. We presented a mathematical model that consists of a standard positive feedback loop with changes of histone modifications during with cell cycling. Based on the model, nucleosome state of an associated gene is a random process during cell cycling, and hence introduces an inherent noise to gene expression, which can automatically induce cell-type switches in cell cycling. Our model reveals a simple mechanism of spontaneous cell-type switches through a stochastic histone modification inheritance during cell cycle. This mechanism is inherent to the normal cell cycle process, and is independent to the external signals.

systems biology↗

bioRxiv2018

Impact of fruit-tree shade intensity on the growth, yield, and quality of intercropped wheat

Agroforestry is a common traditional practice in China-especially in the southern Xinjiang of Northwest China. However, the productivity of many agroforestry systems has been lower than expected in recent years, highlighting the need for an actionably deep mechanistic understanding of the competition between crops and trees. Here, we chose 3 different fruit tree/wheat intercropping agroforestry systems to investigate influence of different fruit tree shade intensity on the growth, yield and quality of intercropping wheat: jujube/wheat, apricot /wheat, and walnut /wheat. We found that compared to the monoculture wheat system, the mean daily shade intensity of the jujube-, apricot-, and walnut-based intercropping systems were, respectively, 23.2%, 57.5%, and 80.7% shade. The photosynthetic rate of wheat in the jujube-, apricot-, and walnut-based intercropping systems decreased by, respectively, 11.3%, 31.9%, and 36.2% compared to monoculture wheat, and the mean number of fertile florets per spike decreased by 26.4%, 37.4%, and 49.5%. Moreover, the apricot- and walnut-based intercropping systems deleteriously affected grain yield (constituent components spike number, grains per spike, and thousand grain weight) and decreased the total N, P, and K content of intercropping wheat. Tree shading intensity strongly enhanced the protein content, wet gluten content, falling number, dough development time, and dough stability time of wheat, but significantly decreased the softening degree. Strong negative linear correlations were observed between tree shade intensity and the number of fertile florets, grain yield (including spike number, grains per spike, and thousand grain weight), nutrient content (N, P and K), and softening degree of wheat. In contrast, we found that daily shade intensity was positively linearly correlated with protein content, wet gluten content, falling number, dough development time, and dough stability time. We conclude that jujube-based intercropping systems can be practical in the region, as they do not decrease the yield and quality of intercropping wheat. Further research should focus on the above-ground/below-ground interspecific interactions and the mechanisms behind the observations that we observed amongst the intercropping systems.

physiology↗

bioRxiv2018

Semi-soft Clustering of Single Cell Data

Motivated by the dynamics of development, in which cells of recognizable types, or pure cell types, transition into other types over time, we propose a method of semi-soft clustering that can classify both pure and intermediate cell types from data on gene expression or protein abundance from individual cells. Called SOUP, for Semi-sOft clUstering with Pure cells, this novel algorithm reveals the clustering structure for both pure cells, which belong to one single cluster, as well as transitional cells with soft memberships. SOUP involves a two-step process: identify the set of pure cells and then estimate a membership matrix. To find pure cells, SOUP uses the special block structure the K cell types form in a similarity matrix, devised by pairwise comparison of the gene expression profiles of individual cells. Once pure cells are identified, they provide the key information from which the membership matrix can be computed. SOUP is applicable to general clustering problems as well, as long as the unrestrictive modeling assumptions hold. The performance of SOUP is documented via extensive simulation studies. Using SOUP to analyze two single cell data sets from brain shows it produce sensible and interpretable results.

genetics↗

bioRxiv2018

Regulation by competition: a hidden layer of gene regulatory network

Molecular competition is ubiquitous, essential and multifunctional throughout diverse biological processes. Competition brings about trade-offs of shared limited resources among the cellular components, and it thus introduce a hidden layer of regulatory mechanism by connecting components even without direct physical interactions. By abstracting the analogous competition mechanism behind diverse molecular systems, we built a unified coarse-grained competition motif model to systematically compare experimental evidences in these processes and analyzed general properties shared behind them. We could predict in what molecular environments competition would reveal threshold behavior or display a negative linear dependence. We quantified how competition can shape regulator-target dose-response curve, modulate dynamic response speed, control target expression noise, and introduce correlated fluctuations between targets. This work uncovered the complexity and generality of molecular competition effect, which might act as a hidden regulatory mechanism with multiple functions throughout biological networks in both natural and synthetic systems.

systems biology↗

bioRxiv2017

A Unified Statistical Framework for Single Cell and Bulk RNA Sequencing Data

Recent advances in technology have enabled the measurement of RNA levels for individual cells. Compared to traditional tissue-level bulk RNA-seq data, single cell sequencing yields valuable insights about gene expression profiles for different cell types, which is potentially critical for understanding many complex human diseases. However, developing quantitative tools for such data remains challenging because of high levels of technical noise, especially the \"dropout\" events. A \"dropout\" happens when the RNA for a gene fails to be amplified prior to sequencing, producing a \"false\" zero in the observed data. In this paper, we propose a Unified RNA-Sequencing Model (URSM) for both single cell and bulk RNA-seq data, formulated as a hierarchical model. URSM borrows the strength from both data sources and carefully models the dropouts in single cell data, leading to a more accurate estimation of cell type specific gene expression profile. In addition, URSM naturally provides inference on the dropout entries in single cell data that need to be imputed for downstream analyses, as well as the mixing proportions of different cell types in bulk samples. We adopt an empirical Bayes approach, where parameters are estimated using the EM algorithm and approximate inference is obtained by Gibbs sampling. Simulation results illustrate that URSM outperforms existing approaches both in correcting for dropouts in single cell data, as well as in deconvolving bulk samples. We also demonstrate an application to gene expression data on fetal brains, where our model successfully imputes the dropout genes and reveals cell type specific expression patterns.

genetics↗

bioRxiv2017

Collaborations between CpG sites in DNA methylation

DNA methylation patterns have profound impacts on genome stability, gene expression, and development. The molecular base of DNA methylation patterns has long been focused at single CpG sites level. Here, we construct a kinetic model of DNA methylation with collaborations between CpG sites, from which a correlation function was established based on experimental data. The function consists of three parts that suggest three possible sources of the correlation: movement of enzymes along DNA, collaboration between DNA methylation and nucleosome modification, and global enzyme concentrations within a cell. Moreover, the collaboration strength between DNA methylation and nucleosome modification is universal for mouse early embryo cells. The obtained correlation function provide insightful understanding for the mechanisms of inheritance of DNA methylation patterns.

genetics↗

bioRxiv2017

Near-Atomic Resolution Structure Determination in Over-Focus with Volta Phase Plate by Cs-corrected Cryo-EM

Volta phase plate (VPP) is a recently developed transmission electron microscope (TEM) apparatus that can significantly enhance the image contrast of biological samples in cryo-electron microscopy (cryo-EM) therefore impose the possibility to solve structures of relatively small macromolecules at high resolution. In this work, we performed theoretical analysis and found that using phase plate on objective lens spherical aberration (Cs)-corrected TEM may gain some interesting optical properties, including the over-focus imaging of macromolecules. We subsequently evaluated the imaging strategy of frozen-hydrated apo-ferritin with VPP on a Cs-corrected TEM and obtained the structure of apo-ferritin at near atomic resolution from both under- and over-focused dataset, illustrating the feasibility and new potential of combining VPP with Cs-corrected TEM for high resolution cryo-EM.\n\nHighlightsThe successful combination of volta phase plate and Cs-corrector in single particle cryo-EM.\n\nNear-atomic structure determined from over-focused images by cryo-EM. VPP-Cs-corrector coupled EM provides interesting optical properties.\n\nIn BriefWe took the unique advantage of the optical system by combining the volta phase plate and Cs-corrector in a modern TEM to collect high resolution micrographs of frozen-hydrated apo-ferritin in over-focus imaging conditions and determined the structure of apo-ferritin at 3.0 Angstrom resolution.

biophysics↗