DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.

Existing methodologies for human induced pluripotent stem cell (hiPSC) cardiac differentiation are efficient but require the use of complex, undefined medium constituents that hinder further elucidation of the molecular mechanisms of cardiomyogenesis. Using hiPSCs derived under chemically defined conditions on synthetic matrices, we systematically developed a highly optimized cardiac differentiation strategy, employing a chemically defined medium consisting of just three components: the basal medium RPMI 1640, L-ascorbic acid 2-phosphate, and rice-derived recombinant human albumin. Along with small molecule-based differentiation induction, this protocol produced contractile sheets of up to 95% TNNT2+ cardiomyocytes at a yield of up to 100 cardiomyocytes for every input pluripotent cell, and was effective in 11 hiPSC lines tested. This is the first fully chemically defined platform for cardiac specification of hiPSCs, and allows the elucidation of cardiomyocyte macromolecular and metabolic requirements whilst providing a minimally complex system for the study of maturation and subtype specification.

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019 (refs 1-3). Since then, COVID-19 has spread rapidly worldwide and has become a global pandemic affecting >200 countries and territories, with an unprecedented effect not only on public health, but also social and economic activities. The exponential increase in the number of patients with COVID-19 in the past 6 months has overwhelmed health-care systems in numerous countries across the world. At present, preventive vaccines and prophylactic therapies for COVID-19 are not available. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a member of the genus Betacoronavirus like the two other coronaviruses that have caused pandemic diseases (severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)) 1-4. As with SARS-CoV and MERS-CoV, SARS-CoV-2 causes a respiratory infection, which leads to viral pneumonia and acute respiratory distress syndrome (ARDS) in some patients 1. However, in addition to respiratory symptoms, uncontrolled SARS-CoV-2 infection can trigger a cytokine storm, whereby pro-inflammatory cytokines and chemokines such as tumour necrosis factor-α, IL-1β and IL-6 are overproduced by the immune system, resulting in multiorgan damage 5. Furthermore, COVID-19 causes coagulation abnormalities in a substantial proportion of patients, which can lead to thromboembolic events 6,7. The genomic sequence 1-3,8 and viral protein structure 9-11 of SARS-CoV-2 have been studied intensively since its emergence. To date, research shows that SARS-CoV-2 shares many biological features with SARS-CoV owing to 79.6% genomic sequence identity 1,2. In particular, both SARS-CoV and SARS-CoV-2 use the same system of cell entry, which is triggered by binding of the viral spike (S) protein to angiotensin-converting enzyme 2 (ACE2) on the surface of the host cell 4. Understanding the biological features of the virus will contribute to the development of diagnostic tests, vaccines and pharmacological therapies and can further our knowledge of tissue tropism. Early clinical data indicate that both the susceptibility to and the outcomes of COVID-19 are strongly associated with cardiovascular disease (CVD) 12-16. A high prevalence of pre-existing Acute respiratory distress syndrome (ArDs). A type of severe, acute respiratory failure characterized by bilateral pulmonary infiltrates and severe hypoxaemia that occurs as a result of illness or injury. Cytokine storm A form of severe immune reaction characterized by overproduction of cytokines and chemokines that can be triggered by a variety of factors such as infection and drugs.

AUTHOR CONTRIBUTIONS R.C.W. designed and performed all scRNAseq experiments, analyzed the scRNAseq data, performed the RNAscope in-situ hybridization assays, performed and analyzed the CITE-seq and FACS experiments, analyzed the immunofluorescence data, performed the eQTL analyses, assisted with mouse colony breeding, drafted the manuscript, and led the study. D.W. assisted with the design of the scRNAseq experiments and performed scRNAseq capture and library preparation for all samples. D.T.P. performed scRNAseq capture and helped obtain human coronary samples. J.C. assisted with the scRNAseq capture, library preparation and sequencing. T.N. performed qPCR experiments, analyzed the qPCR data and performed TCF21 ChIPseq. M.P., C.L.M., B.L. and S.B.M. performed the eQTL analyses. R.K. performed the immunohistochemistry experiments and bred the mouse colonies. M.N. performed and analyzed immunohistochemistry experiments. K.Z., M.A. and R.C. assisted with network analysis. T.K.K., R.F. and Y.J.W. prepared the human tissue samples. M.D.T. and J.C.W. provided critical expert guidance on the manuscript. J.B.K. helped plan the mouse in situ histology studies, managed the mouse colonies, performed the TCF21 over-expression experiment and performed the quantitative immunohistochemistry analysis of lesion characteristics. T.Q. conceived and supervised the study. All authors discussed the results and contributed critical review to the manuscript.