Jul 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 5 references
Medicine
Abstract
In a recent study published in Nature, Chen et al. introduced CHARM (single-cell assay for Chromatin conformation, Histone modi fi cation, chromatin Accessibility, and RNA expression Multi-omics pro fi ling), a platform that simultaneously captures four regulatory modalities within the same nucleus. 1 This integrated strategy provides a comprehensive framework for dissecting how multiple layers of epigenetic regulation converge to control gene expression at single-cell resolution. Gene regulation in eukaryotic cells is governed by a complex interplay of molecular and spatial mechanisms. Chromatin accessibility determines whether regulatory elements such as promoters and enhancers are available for transcription factor binding. Histone modi fi cations de fi ne chromatin states that either promote or repress transcription. In parallel, the three-dimensional organization of the genome establishes spatial proximity between distal regulatory elements and their target genes. Although each of these regulatory layers has been extensively studied, understanding how they operate together within the same cell has remained a major challenge. 2 Previous technologies have provided valuable insights into individual modalities. ATAC-seq pro fi les chromatin accessibility, CUT&Tag captures histone modi fi cations, and Hi-C reveals three-dimensional genome architecture. Recent single-cell platforms such as ChAIR and scHiCAR jointly pro fi le chromatin accessibility, RNA, and 3D contacts, but their 3D contact capture is anchored at accessible chromatin or candidate cis-regulatory elements, introducing structural bias into chromatin architecture reconstruction. 3,4 Moreover, regulatory modalities not captured by these platforms, such as histone modi fi cations, require separate pro fi ling and computational integration for broader cross-modality analysis. CHARM is distinguished from previous platforms by adding histone modi fi cation as a fourth same-cell modality and by using restriction-enzyme-based Hi-C
Nucleosomes organize genomes and regulate DNA access, yet accumulating evidence suggests that their constituent histones may have functions beyond canonical chromatin regulation, but the breadth of such regulatory diversity remains unclear. Here, we used the six-residue loop 2 (L2) of H2A and H2A.Z to map, at single-residue resolution, how nucleosome-core variation reshapes cellular function. Genome-scale interaction mapping identified hundreds of regulatory connections spanning chromatin, as well as actin organization, endocytosis, and membrane trafficking. Interactions were residue-specific and differed between H2A and H2A.Z, revealing a regulatory landscape encoded by single residues. Transcriptome profiling showed limited expression changes and little overlap between differentially expressed genes and regulatory partners, indicating that non-chromatin connections are not readily explained by altered transcription. L2 substitutions also preferentially conferred benefits under cell wall and membrane stress. Thus, the nucleosome is linked to cellular-periphery functions beyond classical chromatin regulation, identifying histone variation as a source of phenotypic innovation.
Zachary H. Harvey, Benjamin Gundinger, Jian-Yi Kok et al.· bioRxiv· 0 citations
The RNA-DNA interactome is established as a new genome regulatory layer that defines and maintains cellular identity and behavior and is shown to be highly dynamic yet reproducibly organized in cell-type specific networks.
A. Lambolez, P. Sahlén, Wenjing Kang et al.· bioRxiv· 0 citations
Abstract The eukaryotic genome is replicated according to a tightly regulated temporal program that ensures each DNA segment is copied once per cell cycle. This program reflects the coordinated action of replication origin licensing, chromatin state, transcriptional activity, and nuclear organisation. While the core mechanisms of licensing and initiation are well characterised, the determinants of origin selection and firing time remain incompletely understood. In budding yeast, origins are defined by specific DNA elements and chromatin features, whereas in metazoans, origin specification is largely sequence-independent and influenced by epigenetic and three-dimensional genome architecture. This review summarises current knowledge of how replication timing is established, regulated, and functionally integrated with chromatin states across eukaryotes, with emphasis on chromatin accessibility, histone modifications and variants, transcriptional regulators, and higher-order genome topology. It also highlights recent genome-wide approaches that map origin licensing, usage, and nascent DNA synthesis at high resolution, revealing dynamic connections between replication, transcription, and nuclear compartmentalisation. Finally, we discuss how disrupted replication timing contributes to replication stress, genome instability, ageing, and cancer. By integrating findings from diverse eukaryotic systems, this provides an updated framework for understanding replication timing as a key layer of genome regulation.
Anne Soeding, Lia Willerding, Lea Riemann et al.· Biological chemistry· 0 citations
A comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts is provided and a hierarchical framework that distinguishes between 'first-level' and 'higher-order' chromatin remodeling is proposed.
