Correction: Fundamental and practical approaches for single-cell ATAC-seq analysis.

[This corrects the article DOI: 10.1007/s42994-022-00082-5.].

Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer's disease.

The blood-brain barrier (BBB) is primarily manifested by a variety of physiological properties of brain endothelial cells (ECs), but the molecular foundation for these properties remains incompletely clear. Here, we generate a comprehensive molecular atlas of adult brain ECs using acutely purified mouse ECs and integrated multi-omics. Using RNA sequencing (RNA-seq) and proteomics, we identify the transcripts and proteins selectively enriched in brain ECs and demonstrate that they are partially correlated. Using single-cell RNA-seq, we dissect the molecular basis of functional heterogeneity of brain ECs. Using integrative epigenomics and transcriptomics, we determine that TCF/LEF, SOX, and ETS families are top-ranked transcription factors regulating the BBB. We then validate the identified brain-EC-enriched proteins and transcription factors in normal mouse and human brain tissue and assess their expression changes in mice with Alzheimer's disease. Overall, we present a valuable resource with broad implications for regulation of the BBB and treatment of neurological disorders.

Fundamental and practical approaches for single-cell ATAC-seq analysis.

Assays for transposase-accessible chromatin through high-throughput sequencing (ATAC-seq) are effective tools in the study of genome-wide chromatin accessibility landscapes. With the rapid development of single-cell technology, open chromatin regions that play essential roles in epigenetic regulation have been measured at the single-cell level using single-cell ATAC-seq approaches. The application of scATAC-seq has become as popular as that of scRNA-seq. However, owing to the nature of scATAC-seq data, which are sparse and noisy, processing the data requires different methodologies and empirical experience. This review presents a practical guide for processing scATAC-seq data, from quality evaluation to downstream analysis, for various applications. In addition to the epigenomic profiling from scATAC-seq, we also discuss recent studies in which the function of non-coding variants has been investigated based on cell type-specific cis-regulatory elements and how to use the by-product genetic information obtained from scATAC-seq to infer single-cell copy number variants and trace cell lineage. We anticipate that this review will assist researchers in designing and implementing scATAC-seq assays to facilitate research in diverse fields.

Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues.

Coronavirus disease 2019 continues to spread worldwide. Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell-derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug-induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA-seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high-throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir-induced cardiotoxicity.