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The vast neuronal diversity in the human neocortex is vital for high-order brain functions, necessitating elucidation of the regulatory mechanisms underlying such unparalleled diversity. However, recent studies have yet to comprehensively reveal the diversity of neurons and the molecular logic of neocortical origin in humans at single-cell resolution through profiling transcriptomic or epigenomic landscapes, owing to the application of unimodal data alone to depict exceedingly heterogeneous populations of neurons. In this study, we generated a comprehensive compendium of the developing human neocortex by simultaneously profiling gene expression and open chromatin from the same cell. We computationally reconstructed the differentiation trajectories of excitatory projection neurons of cortical origin and inferred the regulatory logic governing lineage bifurcation decisions for neuronal diversification. We demonstrated that neuronal diversity arises from progenitor cell lineage specificity and postmitotic differentiation at distinct stages. Our data paves the way for understanding the primarily coordinated regulatory logic for neuronal diversification in the neocortex.

Abstract Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin’s lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to “Watson–Crick” base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL. Graphical abstract

Whole genome bisulfite sequencing (WGBS) is an essential technique for methylome studies. Although a series of tools have been developed to overcome the mapping challenges caused by bisulfite treatment, the latest available tools have not been evaluated on the performance of reads mapping as well as on biological insights in multiple mammals. Herein, based on the real and simulated WGBS data of 14.77 billion reads, we undertook 936 mappings to benchmark and evaluate 14 wildly utilized alignment algorithms from reads mapping to biological interpretation in humans, cattle and pigs: Bwa-meth, BSBolt, BSMAP, Walt, Abismal, Batmeth2, Hisat_3n, Hisat_3n_repeat, Bismark-bwt2-e2e, Bismark-his2, BSSeeker2-bwt, BSSeeker2-soap2, BSSeeker2-bwt2-e2e and BSSeeker2-bwt2-local. Specifically, Bwa-meth, BSBolt, BSMAP, Bismark-bwt2-e2e and Walt exhibited higher uniquely mapped reads, mapped precision, recall and F1 score than other nine alignment algorithms, and the influences of distinct alignment algorithms on the methylomes varied considerably at the numbers and methylation levels of CpG sites, the calling of differentially methylated CpGs (DMCs) and regions (DMRs). Moreover, we reported that BSMAP showed the highest accuracy at the detection of CpG coordinates and methylation levels, the calling of DMCs, DMRs, DMR-related genes and signaling pathways. These results suggested that careful selection of algorithms to profile the genome-wide DNA methylation is required, and our works provided investigators with useful information on the choice of alignment algorithms to effectively improve the DNA methylation detection accuracy in mammals.

Abstract Background Histone post-translational modifications play crucial roles in epigenetic regulation of gene expression and are known to be associated with the phenotypic differences of different cell types. Therefore, it is of fundamental importance to dissect the genes and pathways involved in such a phenotypic variation at the level of epigenetics. However, the existing comparative approaches are largely based on the differences, especially the absolute difference in the levels of individual histone modifications of genes under contrasting conditions. Thus, a method for measuring the overall change in the epigenetic circumstance of each gene underpinned by multiple types of histone modifications between cell types is lacking. Results To address this challenge, we developed ICGEC, a new method for estimating the degree of epigenetic conservation of genes between two cell lines. Different from existing comparative methods, ICGEC provides a reliable score for measuring the relative change in the epigenetic context of corresponding gene between two conditions and simultaneously produces a score for each histone mark. The application of ICGEC to the human embryonic stem cell line H1 and four H1-derived cell lines with available epigenomic data for the same 16 types of histone modifications indicated high robustness and reliability of ICGEC. Furthermore, the analysis of the epigenetically dynamic and conserved genes which were defined based on the ICGEC output results demonstrated that ICGEC can deepen our understanding of the biological processes of cell differentiation to overcome the limitations of traditional expression analysis. Specifically, the ICGEC-derived differentiation-direction-specific genes were shown to have putative functions that are well-matched with cell identity. Additionally, H3K79me1 and H3K27ac were found to be the main histone marks accounting for whether an epigenetically dynamic gene was differentially expressed between two cell lines. Conclusions The use of ICGEC creates a convenient and robust way to measure the overall epigenetic conservation of individual genes and marks between two conditions. Thus, it provides a basis for exploring the epigenotype-phenotype relationship. ICGEC can be deemed a state-of-the-art method tailored for comparative epigenomic analysis of changes in cell dynamics.