Dissecting Human Gonadal Cell Lineage Specification and Sex Determination Using A Single-cell RNA-seq Approach

Gonadal somatic cells are the main players in gonad development and are important for sex determination and germ cell development. Here, using a time-series single-cell RNA sequencing(scRNA-seq) strategy, we analyzed fetal germ cells(FGCs) and gonadal somatic cells in human embryos and fetuses. Clustering analysis of testes and ovaries revealed several novel cell subsets,including POU5F1+SPARC+FGCs and KRT19+somatic cells. Furthermore, our data indicated that the bone morphogenetic protein(BMP) ...     

High histone variant H3.3 content in mouse prospermatogonia suggests a role in epigenetic reformatting

Histone variants can incorporate into the nucleosome outside of S-phase. Some are known to play important roles in mammalian germ cell development, this cell lineage being characterized by long phases of quiescence, a protracted meiotic phase, and genome-wide epigenetic reformatting events. The best known example of such an event is the global-scale erasure of DNA methylation in sexually indifferent primordial germ cells, then its re-establishment in fetal prospermatogonia and growing oocytes. Histone H3 and its post-translationally modified forms provide important waypoints in the establishment of epigenetic states. Using mass spectrometry and immunoblotting, we show that the H3.3 replacement variant is present at an unusually high amount in mouse prospermatogonia at the peak stage of global DNA methylation re-establishment. We speculate that H3.3 facilitates this process through achieving a greater level of accessibility of chromatin modifiers to DNA.     

多组学大数据整合分析揭示早期胚胎发育过程中基因表达调控信息的变化规律

摘要 目的：探究哺乳动物早期胚胎发育过程中基因表达调控信息的变化规律。方法：收集小鼠早期胚胎发育各时期的RNA-seq,ATAC-seq,MethylC-Seq和H3K4me3 ChIP-seq数据进行整合分析,观察小鼠早期胚胎发育各时期转录因子表达量的变化,计算各时期基因表达量与转录因子结合位点数量及染色质可及性的相关性,筛选各时期表达量前10%的基因,统计其表达量和转录因子占比,并进行启动子可及性分析。根据前期报道的转录因子三节点调控网络,对早期胚胎各时期转录因子调控网络的富集模式进行分析。根据多组学数据分析结果,推测早期胚胎发育调控过程中转录因子和表观遗传修饰信息的共调控模型。结果：转录因子数量和调控关系变化以及染色质可及性、DNA甲基化修饰、组蛋白修饰等表观遗传修饰共同调控早期胚胎发育各时期的基因表达,这些因素在不同时期发挥不同程度的调控作用。结论：转录因子和表观遗传修饰在早期胚胎发育过程中动态调控基因表达。     

Flexible copula model for integrating correlated multi-omics data from single-cell experiments

With recent advances in technologies to profile multi-omics data at the single-cell level, integrative multi-omics data analysis has been increasingly popular. It is increasingly common that information such as methylation changes, chromatin accessibility, and gene expression are jointly collected in a single-cell experiment. In biomedical studies, it is often of interest to study the associations between various data types and to examine how these associations might change according to other factors such as cell types and gene regulatory components. However, since each data type usually has a distinct marginal distribution, joint analysis of these changes of associations using multi-omics data is statistically challenging. In this paper, we propose a flexible copula-based framework to model covariate-dependent correlation structures independent of their marginals. In addition, the proposed approach could jointly combine a wide variety of univariate marginal distributions, either discrete or continuous, including the class of zero-inflated distributions. The performance of the proposed framework is demonstrated through a series of simulation studies. Finally, it is applied to a set of experimental data to investigate the dynamic relationship between single-cell RNA sequencing, chromatin accessibility, and DNA methylation at different germ layers during mouse gastrulation.     

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome‐wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA‐ and histone‐modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.     

Epigenetic transitions in germ cell development and meiosis

Germ cell development is controlled by unique gene expression programs and involves epigenetic reprogramming of histone modifications and DNA methylation. The central event is meiosis, during which homologous chromosomes pair and recombine, processes that involve histone alterations. At unpaired regions, chromatin is repressed by meiotic silencing. After meiosis, male germ cells undergo chromatin remodeling, including histone-to-protamine replacement. Male and female germ cells are also differentially marked by parental imprints, which contribute to sex determination in insects and mediate genomic imprinting in mammals. Here, we review epigenetic transitions during gametogenesis and discuss novel insights from animal and human studies.