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Abstract An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We find the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.

Cancer-associated fibroblasts (CAFs) are the main component of the stroma in pancreatic cancer, but their tissue of origin remains to be defined. Here the authors perform lineage tracing and single cell RNA sequencing in mice and suggest the splanchnic mesenchyme as the tissue of origin for CAFs.

Here the authors provide a multi-omic study of the nucleosome landscape in LNCaP cells and observe nine functional nucleosome states each with characteristic nucleosome footprints. Upon androgen stimulation, they observed changes in these nucleosome states accompanied by changes in binding and function of pioneer factors, including GATA2.

In breast cancer, the 3D architecture of the genome can impact gene regulation. Here, the authors use tethered chromatin conformation profiling to investigate 3D chromatin structure in models of hormone-induced breast cancer and endocrine resistance, finding dynamic temporal reorganisation.

The vast majority of BRCA1-driven breast cancers derive from luminal progenitor cells but the mechanisms of this lineage specificity are unclear. Here the authors show that dangerous accumulation of DNA-RNA hybrid structures due to RNA polymerase II pausing, occurs specifically in luminal epithelial cells.

Abstract Despite numerous studies done on understanding the role of DNA methylation, limited work has focused on systems integration of cell type-specific interplay between DNA methylation and gene transcription. Through a genome-wide analysis of DNA methylation across 19 cell types with T-47D as reference, we identified 106,252 cell type-specific differentially-methylated CpGs categorized into 7,537 differentially (46.6% hyper- and 53.4% hypo-) methylated regions. We found 44% promoter regions and 75% CpG islands were T-47D cell type-specific methylated. Pyrosequencing experiments validated the cell type-specific methylation across three benchmark cell lines. Interestingly, these DMRs overlapped with 1,145 known tumor suppressor genes. We then developed a Bayesian Gaussian Regression model to measure the relationship among DNA methylation, genomic segment distribution, differential gene expression and tumor suppressor gene status. The model uncovered that 3′UTR methylation has much less impact on transcriptional activity than other regions. Integration of DNA methylation and 82 transcription factor binding information across the 19 cell types suggested diverse interplay patterns between the two regulators. Our integrative analysis reveals cell type-specific and genomic region-dependent regulatory patterns and provides a perspective for integrating hundreds of various omics-seq data together.

COBRA1 is a BRCA1-binding protein and, as part of the negative elongation factor, regulates RNA polymerase II pausing and transcription elongation. Here, the authors show that tissue-specific deletion of mouse Cobra1 inhibits postnatal mammary gland development and that the mammary defects can be rescued by additional deletion of Brca1in a DNA repair-independent manner.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nature Communications 8: Article number: 15908 (2017); Published 26 June 2017; Updated 30 March 2018 The original version of this Article omitted the following from the Acknowledgements: ‘The work was also supported by a grant to Y.H. from the Cancer Prevention Research Institute of Texas CPRIT RP170126.