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Inner side of TADs revealed by super-resolution microscopy
The genome undergoes three-dimensional organization and folds into topologically associating domains (TADs). However, the nature and folding of TADs in single cells have remained obscure. The use of optical super-resolution microscopy has revealed that averaged TADs identified through Hi-C (represented here inside the prism) emerge from a wide variety of individual TAD structures that have diverse shapes and can be subdivided into heterogeneous chromatin nanodomains (seen here as the structures emerging from the diffracted light ray). Furthermore, quantitative microscopy enables dissection of the roles of CTCF, cohesin and nucleosome interactions in the regulation of TAD and chromatin nanodomain architecture, illustrating the power of imaging to reveal single-cell genome organization.
Given an opportunity to chronicle the experience of traversing America as a Black man, I elect to convey a less frequently told vantage point. This is the perspective of the ‘accomplished’ bootless.
Patterns of co-occurring and mutually exclusive mutations reveal synergistic interactions among cancer driver genes. A new study functionally confirms these interactions and builds the pairwise relationships into networks of pathway disruption that have better predictive power than specific mutations alone.
In a classical view of carcinogenesis, carcinogens directly cause mutations. In this issue, Riva et al. explore the effects of 20 known or suspected human carcinogens and find discernible mutational signatures for only three of them.
This Perspective explores the concept of tumor promotion and shows how carcinogenesis experiments performed decades ago in mice are remodeling the view of cancer initiation and prevention.
Analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes shows an enrichment of rare nonsynonymous secondary variants in the same gene set, with significant over-representation of secondary alleles in chaperonin-encoding genes.
Super-resolution microscopy identifies sub-topologically associating domain (TAD) nanodomains and intercellular heterogeneity in TAD conformation and insulation. Cohesin or CTCF depletion regulates distinct types of chromatin contacts at the TAD but not nanodomain level.
Single-cell chromatin profiling of different brain regions identifies cell-type-specific regulatory elements, and helps to predict functional SNPs for Alzheimer’s and Parkinson’s diseases.
Genome-wide association analyses in the Japanese population and trans-ancestry meta-analyses identify new risk loci for coronary artery disease. A polygenic risk score derived from these findings identifies individuals with increased risk of long-term cardiovascular mortality.
Somatic mutational loads in cancer genomes change with chromatin domain boundaries. Different mutational processes lead to distinct somatic mutation distributions in active versus inactive domains, including during tumor evolution.
A genomic analysis of tumors in mice caused by known or suspected carcinogens shows that most carcinogens do not generate distinct mutational signatures.
Computational analysis of over 9,000 cancer genomes, coupled with functional validation in cell lines, highlights combinations of mutations required for tumor progression. This integrated approach provides a framework to stratify patients on the basis of interdependent genetic aberrations.
Single-cell RNA-seq of a collection of 200 cancer cell lines finds common, recurrent heterogeneous expression programs, which also are found in patient samples and are linked to cell state and drug sensitivity.
Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.
High-throughput chromosome conformation enhancer capture identifies dynamic enhancer networks that regulate differentiation of human mesenchymal stem cells. Transcription factors (TFs) at baited enhancers appear to stabilize TF binding at target enhancers.
MR-JTI, a unified framework for joint-tissue imputation and Mendelian randomization, improves prediction performance in a tissue-dependent manner when applied to large-scale biobanks and meta-analysis data.
CHESS is an algorithm that compares chromatin contact maps and identifies differential features. It can analyze interspecies syntenic regions and three-dimensional changes caused by genetic perturbation.
PolyGembler, a method for grouping and ordering contigs into complete pseudomolecules by combining long-read sequencing and genotype information from an outbred mapping population, improves the accuracy for assembly of polyploidy plant genomes.