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Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: SPRY1 is associated with the invasiveness and prognosis of various tumors, and TET3 affects aging by regulating gene expression. Aims: We investigated the roles of SPRY1 and TET3 in natural skin aging, replicative aging, and photoaging, along with the effect of UVA on genome‐wide DNA methylation in HaCaT cells. Methods: TET3 and SPRY1 expression were measured in the skin of patients of different age groups, as well as in vitro human skin, HaCaT cell replicative senescence, and HaCaT and HaCaT‐siTET3 cell photoaging models. Senescence was verified using β‐galactosidase staining, and DNA damage was detected using immunofluorescence staining for γ‐H2A.X. 5‐Methyl cytosine (5‐mC) content in the genome was determined using ELISA. Results: SPRY1 expression increased with age, whereas TET3 expression decreased. Similarly, SPRY1 was upregulated and TET3 was downregulated with increasing cell passages. TET3‐siRNA upregulated SPRY1 expression in HaCaT cells. UVA irradiation promoted HaCaT cell senescence and induced cellular DNA damage. SPRY1 was upregulated and TET3 was downregulated upon UVA irradiation. Genome‐wide 5‐mC content increased upon TET3 silencing and UVA irradiation, indicating a surge in overall methylation. Conclusions: SPRY1 and TET3 are natural skin aging‐related genes that counteract to regulate replicative aging and UVA‐induced photoaging in HaCaT cells. The cell photoaging model may limit experimental bias caused by different exposure times of skin model samples. [ABSTRACT FROM AUTHOR]

The article discusses a study on single-cell DNA methylation and 3D genome architecture in the human brain. The research provides a comprehensive atlas of epigenomic characteristics, revealing cell-type specificity, chromatin structures, and DNA methylation patterns, which will be valuable for understanding brain cell diversity, gene regulation mechanisms, and the development of genetic tools.