bims-crepig 2026-02-08 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2026–02–08
sixteen papers selected by
Connor Rogerson, University of Cambridge

The chromatin remodeller CHD4 regulates transcription factor binding to both prevent activation of silent enhancers and maintain active regulatory elements.
EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity.
Regulatory grammar in human promoters uncovered by MPRA-based deep learning.
FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity.
An integrated multi-omics and network analysis of neutrophil differentiation from initial- to late-stage.
esBAF and INO8°C fine-tune subcompartments and differentially regulate enhancer-promoter interactions.
Cohesin-mediated chromatin organization controls the differentiation and function of dendritic cells.
Transient histone deacetylase inhibition induces cellular memory of gene expression and 3D genome folding.
An experimentally-informed polymer model reveals high resolution organization of genomic loci.
A genetic screen for modifiers of cohesin clustering identifies regulators of genome folding.
Dual promoter-enhancer activities reflect a unified regulatory logic.
Deciphering hierarchical regulatory network of cell fate via an epigenetics-informed heterogeneous graph transformer on single-cell multi-omics data.
Boosting the detection of enhancer-promoter loops via normalization methods for chromatin interaction data.
Differential nucleosome organization in human interphase and metaphase chromosomes.
BiCLUM: Bilateral contrastive learning for unpaired single-cell multi-omics integration.
Single-molecule tracking of DNMT1 in living cells reveals its cell cycle dynamics and its redistribution upon drug treatment.

Elife. 2026 Feb 03. pii: RP109280. [Epub ahead of print]14

The chromatin remodeller CHD4 regulates transcription factor binding to both prevent activation of silent enhancers and maintain active regulatory elements.

Andria Koulle, Oluwaseun Ogundele, Devina Shah, India Baker, Maya Lopez, David Lando, Nicola Reynolds, Ramy Ragheb, Ernest D Laue, Brian Hendrich.

  Chromatin organisation and transcriptional regulation are tightly coordinated processes that are essential for maintaining cellular identity and function. ATP-dependent chromatin remodelling proteins play critical roles in control of genome structure and in regulating transcription across eukaryotes. Their essential nature, however, has made it difficult to define exactly how these functions are mediated. The chromatin remodeller CHD4 has been shown to be capable of sliding nucleosomes in vitro, and to regulate chromatin accessibility and gene expression in vivo. Using an inducible depletion system, here we identify a second mechanism of action for CHD4 in actively restricting the residence time of transcription factors (TFs) on chromatin. Together, these activities result in distinct, context-dependent outcomes: at highly accessible regulatory elements, CHD4 limits TF binding to maintain regulatory function, while at low-accessibility euchromatic regions, it prevents TF engagement and sustains chromatin compaction, thereby silencing cryptic enhancers. Collectively, these mechanisms enable CHD4 to reduce transcriptional noise while preserving the responsiveness of active regulatory networks.

Keywords:  chromatin; chromatin remodelling; chromosomes; embryonic stem cell; enhancer; gene expression; mouse; nucleosome; transcription factors

DOI:  https://doi.org/10.7554/eLife.109280
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2527303123

EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity.

Jeffrey Granat, Sanxiong Liu, Luis Popoca, Ozgur Oksuz, Danny Reinberg.

  Polycomb Repressive Complex 2 (PRC2) facilitates the formation of facultative heterochromatin, instrumental to tissue specific gene expression. PRC2 catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3), which is targeted for chromatin compaction by PRC1. Importantly, PRC2-associated cofactors regulate its distinct activities, as in the case of MTF2 and JARID2 that direct PRC2 to specific chromatin nucleation sites based on preferred DNA-binding motifs. Here, we investigated EPOP whose role in regulating PRC2 was not well-defined. We find that both EPOP and MTF2 stimulate PRC2 histone methyltransferase (HMT) activity in vitro. Unlike MTF2, EPOP is ineffectual in PRC2 chromatin recruitment as evidenced by an EED-rescue system in vivo but promotes H3K27me3 deposition de novo in cooperation with MTF2 and JARID2. Binding assays using reconstituted dinucleosome substrates revealed that similar to MTF2, EPOP promotes PRC2 chromatin-binding activity in a distinct DNA-sequence-dependent manner (GCN-rich and GA-rich, respectively). Thus, EPOP and MTF2 in conjunction with JARID2 foster PRC2-mediated HMT activity at chromatin sites comprising cofactor-preferred DNA-binding sequences during the formation of H3K27me3-chromatin domains.

Keywords:  PRC2; epigenetics; repressive chromatin; transcription

DOI:  https://doi.org/10.1073/pnas.2527303123
Nature. 2026 Feb 04.

Regulatory grammar in human promoters uncovered by MPRA-based deep learning.

Lucía Barbadilla-Martínez, Noud Klaassen, Vinícius H Franceschini-Santos, Jérémie Breda, Hatice Yücel, Miguel Hernández-Quiles, Tijs van Lieshout, Carlos G Urzua Traslaviña, Minh Chau Luong Boi, Maryam Akbarzadeh, Celia Hermana-Garcia-Agullo, Sebastian Gregoricchio, Marcel de Haas, Roy Straver, Sarah Derks, Wilbert Zwart, Emile Voest, Lude Franke, Michiel Vermeulen, Jeroen de Ridder, Bas van Steensel.

Promoters are the core regulatory elements of all genes. Their activity ensures the correct transcription level of each individual gene, which is essential for cellular homeostasis and responses to a wide range of signals. One of the major challenges in genomics is to build computational models that accurately predict genome-wide gene expression from the sequences of regulatory elements1. Here we present promoter activity regulatory model (PARM), a cell-type-specific deep-learning model trained on specially designed massively parallel reporter assays (MPRAs) that query human promoter sequences. PARM is experimentally and computationally lightweight so that cell-type-specific and condition-specific models can be generated that reliably predict autonomous promoter activity across the genome from the DNA sequence alone. PARM can also design purely synthetic strong promoters. We leveraged PARM to systematically identify binding sites of transcription factors that probably contribute to the activity of each natural human promoter and to detect the rewiring of these regulatory interactions after various stimuli to the cells. We also uncovered and experimentally confirmed substantial positional preferences of transcription factors that differ between activating and repressive regulatory functions and a complex grammar of motif-motif interactions. Our approach provides a highly economic strategy towards a deeper understanding of the dynamic regulation of human promoters by transcription factors.

DOI: https://doi.org/10.1038/s41586-025-10093-z
Cell Rep. 2026 Jan 31. pii: S2211-1247(26)00028-8. [Epub ahead of print]45(2): 116950

FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity.

Erik M Ladewig, Abbas Nazir, Tyler Park, Vinson B Fan, Zhendong Cao, Jacob Hawk, Lauren Kelly, Robert Tjian, Christina S Leslie, Charles L Sawyers.

  Mutations in the pioneer transcription factor FOXA1 occur in 10%-40% of prostate cancers and broadly alter chromatin accessibility. In a cohort of 874 primary and metastatic tumors, we confirm frequent Wing2 missense mutations and indels, as well as C-terminal truncating frameshifts. To define their functional impact, we performed single-nucleus multiome profiling in mouse prostate organoids expressing representative alleles, including overexpressed wild-type FOXA1. Each subgroup produces distinct chromatin and transcriptional changes, but all perturb epithelial lineage specification. Indel mutants promote basal-like states, whereas C-terminal truncations, Wing2 missense mutations, and elevated wild-type FOXA1 drive secretory L1-like luminal fates. Integrated RNA-seq, ATAC-seq, and ChIP-seq reveal that L1-like specification involves a hybrid androgen receptor/FOXA1 motif and cooperation with POU2F1. In vivo, these same alleles, combined with Trp53/Pten loss, shift tumor histology from basal-like to secretory luminal phenotypes.

Keywords:  CP: cancer; CP: molecular biology; FOXA1; POU2F1; basal; luminal; prostate

DOI:  https://doi.org/10.1016/j.celrep.2026.116950
Genome Biol. 2026 Jan 30.

An integrated multi-omics and network analysis of neutrophil differentiation from initial- to late-stage.

Qing Chen, Tianchang Yang, Yingping Hou, Kai Wang, Tingting Li, Longteng Wang, Cuiyun Dou, Panpan Cheng, Minglei Shi, Wei Li.

   BACKGROUND: Neutrophil differentiation is a well-orchestrated process that involves coordinated changes in the chromatin accessibility, transcription factor (TF) binding, 3D genome-structure and transcription. However, despite significant advances in understanding the later stages of neutrophil maturation, the initial molecular events that trigger and drive the commitment to neutrophil lineage remain poorly characterized, especially the functional roles of master TFs in orchestrating the earliest stages of lineage specification.
RESULTS: Here, we examine changes in the genome topology, transcriptome, and chromatin accessibility during the neutrophil differentiation process. We demonstrate striking changes in 3D genome structure and chromatin accessibility as early as 4 h after all-trans-retinoic acid treatment, which accommodate and regulate gene expression to guide neutrophil lineage differentiation. Analysis of early transcriptional changes confirmed CEBPA as a key TF. To further elucidate the relationships among CEBPA binding, chromatin accessibility, 3D genomic organization, and gene expression, we perform CEBPA HiCut, a technology that simultaneously profiles TF- DNA binding sites and TF-mediated 3D genome interactions. Our first TF-mediated HiCut experiment in neutrophils revealed the synergistic relationship and sequential regulation cascade between this core TF and chromatin accessibility, 3D genomic organization, and gene expression.
CONCLUSIONS: Our work systematically investigates coordinated chromatin accessibility, TF binding, 3D genome-structure and transcriptional changes during neutrophil differentiation, especially at initialization. Our study highlights the sequential interplay between the initial changes of chromatin state, 3D genome organization and pioneer TF s such as CEBPA.

Keywords:  3D genome; All-trans-retinoic acid; Chromatin accessibility; Gene regulatory network; HL-60; Neutrophil differentiation

DOI:  https://doi.org/10.1186/s13059-025-03902-1
Genetics. 2026 Feb 05. pii: iyag037. [Epub ahead of print]

esBAF and INO8°C fine-tune subcompartments and differentially regulate enhancer-promoter interactions.

Braulio Bonilla, Benjamin J Patty, Snehal V Sambare, Job Dekker, Thomas G Fazzio, Sarah J Hainer.

  The genome is compacted in the nucleus through a hierarchical chromatin organization, ranging from chromosome territories to compartments, topologically associating domains (TADs), and individual nucleosomes. Nucleosome remodeling complexes hydrolyze ATP to translocate DNA and thereby mobilize histone proteins. While nucleosome remodeling complexes have been extensively studied for their roles in regulating nucleosome positioning and accessibility, their contributions to higher-order chromatin architecture remain less well understood. Here, we investigate the roles of two key nucleosome remodelers, esBAF and INO8°C, in shaping 3D genome organization in mouse embryonic stem cells. Using Hi-C, we find that loss of either remodeler has minimal effects on global compartment or TAD structures. In contrast, subcompartment organization is notably altered, suggesting that esBAF and INO8°C contribute to finer-scale chromatin topology. To overcome the limited resolution of Hi-C for detecting regulatory loops, we employed promoter capture Micro-C (PCMC), which revealed that the loss of esBAF or INO8°C alters a subset of promoter anchored looping interactions. Although these changes occur at distinct genomic loci for each remodeler, the affected sites are commonly enriched for bivalent chromatin regions bound by OCT4, SOX2, and NANOG (OSN), as well as BRG1 and INO80 themselves. Together, our findings reveal that esBAF and INO8°C selectively influence subcompartment identity and enhancer-promoter communication at key regulatory loci, highlighting a previously underappreciated role for nucleosome remodelers in higher-order chromatin organization.

Keywords:  chromatin; enhancer-promoter interactions; remodelers; stem cells; subcompartments

DOI:  https://doi.org/10.1093/genetics/iyag037
Sci Immunol. 2026 Feb 06. 11(116): eadx4622

Cohesin-mediated chromatin organization controls the differentiation and function of dendritic cells.

Nicholas M Adams, Aleksandra Galitsyna, Ioanna Tiniakou, Eduardo Esteva, Ai C Ra, Daniel Martinez-Krams, Colleen M Lau, Jojo Reyes, Nezar Abdennur, Alexey Shkolikov, George S Yap, Alireza Khodadadi-Jamayran, Igor Dolgalev, Leonid A Mirny, Boris Reizis.

The cohesin complex extrudes chromatin loops, stopping at sites bound by CCCTC-binding factor (CTCF) and organizing chromosomes into topologically associated domains, yet biological implications of this process remain obscure. We show that cohesin controls the in vivo differentiation and function of murine antigen-presenting dendritic cells (DCs), particularly antigen cross-presentation and interleukin-12 (IL-12) secretion by type 1 conventional DCs (cDC1s). The chromatin organization of DCs was shaped by cohesin and the transcription factor IRF8, which facilitated chromatin looping and chromosome compartmentalization, respectively. Optimal expression of IRF8 itself required CTCF/cohesin binding sites demarcating the Irf8 gene. During DC activation, cohesin enabled the induction of a subset of genes that were preferentially located in Polycomb-repressed regions and enriched in more distal enhancers. Accordingly, deletion of CTCF sites flanking the Il12b gene in mice reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin folding in cell differentiation and function in vivo and its bidirectional cross-talk with lineage-specifying transcription factors.

DOI: https://doi.org/10.1126/sciimmunol.adx4622
Nat Genet. 2026 Feb 04.

Transient histone deacetylase inhibition induces cellular memory of gene expression and 3D genome folding.

Flora Paldi, Michael-Florian Szalay, Solène Dufau, Marco Di Stefano, Hadrien Reboul, Daniel Jost, Frédéric Bantignies, Giacomo Cavalli.

Epigenetic memory enables the propagation of gene expression patterns following transient stimuli. Although three-dimensional chromatin organization is emerging as a key regulator of genome function, it is unknown whether it contributes to cellular memory. Here we establish that acute perturbation of the epigenome can induce cellular memory of gene expression in mouse embryonic stem cells. We uncover how a pulse of histone deacetylase inhibition translates to changes in transcription, histone modifications and genome folding. While most epigenomic and transcriptional changes are initially reversed once the perturbation is removed, some loci remain transcriptionally deregulated and genome architecture partially maintains its perturbed conformation. Consequently, a second pulse of transient hyperacetylation induces stronger memory of transcriptional deregulation. Using ultradeep Micro-C, we associate memory of gene expression with repressive Polycomb-mediated chromatin topology. These results demonstrate how cells can record transient stresses in their genome architecture, thereby enabling an enhanced response to subsequent perturbations.

DOI: https://doi.org/10.1038/s41588-025-02489-4
Nat Commun. 2026 Feb 04.

An experimentally-informed polymer model reveals high resolution organization of genomic loci.

Rahul Mittal, Dieter W Heermann, Arnab Bhattacherjee.

Gene expression patterns are governed by the hierarchical organization of the genome. Numerous efforts, leveraging both polymer physics-based models and experimental imaging technologies, have sought to elucidate the structure-function relationship of chromatin fibers. However, a major challenge is posed by the multi-scale nature of chromatin organization. Here, we present an experimentally informed, polymer physics-based model capable of reconstructing chromatin structural ensembles by integrating low-resolution contact data with MNase-derived nucleosome positioning information. We apply our approach to multiple human genomic loci. Our analysis shows distinct structural features associated with active and inactive chromatin states, providing insights into the relationship between genomic organization and transcriptional activity. These findings offer a framework for understanding genome structure-function relationships.

DOI: https://doi.org/10.1038/s41467-026-68928-w
Sci Adv. 2026 Jan 30. 12(5): eadx5130

A genetic screen for modifiers of cohesin clustering identifies regulators of genome folding.

Wonho Kim, Daniel S Park, Son C Nguyen, Rachel Yang, Eric F Joyce, Rajan Jain.

The cohesin complex orchestrates 3D genome architecture through multiple steps including loading onto chromatin, DNA loop extrusion, stalling of extrusion, and unloading off chromatin. However, the upstream regulatory factors modulating these steps remain largely unexplored. Previous studies suggest that cohesin clustering correlates with its chromatin residence time and loop extrusion activity. Here, we developed, optimized, and performed an imaging-based genetic screen leveraging modulation of cohesin clustering to identify cohesin regulators. Using a sensitized background in which the cohesin unloader WAPL is partially degraded, we screened the druggable genome for effects on cohesin clustering. Through multiple rounds of screening and experimentation, we identified 7 enhancers and 10 suppressors of cohesin clustering. Several factors control genome folding at multiple loci and cohesin loading. Notably, our screen identified factors in mitochondrial function and epigenetic silencing, implicating these processes in the regulation of cohesin activity. This study offers a valuable resource identifying cohesin regulators and provides insights into upstream mechanisms governing genome folding.

DOI: https://doi.org/10.1126/sciadv.adx5130
Nat Commun. 2026 Jan 30.

Dual promoter-enhancer activities reflect a unified regulatory logic.

Mauricio I Paramo, Alden King-Yung Leung, Sagar R Shah, Junke Zhang, Nathaniel D Tippens, Jin Liang, Li Yao, Yiyang Jin, Xiuqi Pan, Abdullah Ozer, John T Lis, Haiyuan Yu.

Accumulating evidence indicates that both putative promoters and enhancers can exert dual promoter and enhancer functions. However, how these activities are related within individual elements and what determines this dual functionality remain poorly understood. We developed a massively parallel dual reporter assay that enables simultaneous assessment of the intrinsic promoter and enhancer potential exerted by the same sequence. Parallel quantification for thousands of elements reveals that canonical human promoters and enhancers can act as both promoters and enhancers under the same contexts, and that promoter activity may be necessary but not sufficient for enhancer function. Perturbations to element transcription factor binding motifs lead to disruptions in both activities, implicating a shared syntax for the two regulatory functions. Combinations of elements with different minimal promoters reveal reciprocal activity modulation, which, together with a strong correlation between promoter and enhancer functions, imply a bidirectional feedback loop to sustain environments of high transcriptional activity. Finally, we validate this reciprocity and correlation in situ using CRISPR activation at the human β-globin locus. Our approach reveals that the functional convergence between promoters and enhancers arises from a shared regulatory logic and sequence syntax, advancing a unified model for regulatory element biology.

DOI: https://doi.org/10.1038/s41467-026-68780-y
Brief Bioinform. 2025 Nov 01. pii: bbaf664. [Epub ahead of print]26(6):

Deciphering hierarchical regulatory network of cell fate via an epigenetics-informed heterogeneous graph transformer on single-cell multi-omics data.

Yuhong Huang, Chao Liu, Zhiling Yang, Bo Liu, Xiao Zhai, Jiajin Zheng, Jing Xiao, Tao Song.

  The precise control of cell fate is driven by a hierarchical regulatory network (HRNet) where transcription factors (TFs) and cis-regulatory elements (CREs) orchestrate the expression of target genes (TGs) through complex causal actions. While single-cell multi-omics technologies provide multi-dimensional data to resolve regulatory networks, existing methods often fail to capture their hierarchical and causal properties. We propose SMOGT (Single-cell Multi-Omics Graph Transformer), a graph representation learning method to decipher HRNet. SMOGT embeds epigenetic mechanism into Heterogeneous Graph Transformer (HGT) by structuring information flow along a hierarchical-guided meta-path (TF-TF → TF-CRE → CRE-CRE → CRE-TG), and employs a semi-supervised strategy to ensure network accuracy. Validated against ChIP-seq and HiC-seq benchmarked datasets, SMOGT showed significantly higher accuracy in predicting transcriptional regulation (TF-CRE) and long-range chromatin conformation (CRE-CRE). The HRNet scaffolds downstream modules that mechanistically link network architecture to cell fate. The multi-layer random walk (MRWR) module identifies driver regulators and their TGs. The BioStreamNet module predicts shifts in cell fate trajectories following in silico perturbations within gene-specific HRNet formed by extracting regulatory weights during TG expression prediction. In hematopoietic stem cell differentiation, SMOGT elucidated the hierarchical causal cascade from driver TFs that governs lineage commitment. In melanoma epithelial-to-mesenchymal transition (EMT), it revealed a critical therapeutic window for reversing the process, and in Acute Myeloid Leukemia (AML), it uncovered hub-CREs with significant prognostic value. By accurately modeling hierarchical causality, SMOGT provides a robust tool to dissect and predict cell fate dynamics in both development and disease.

Keywords:   in silico perturbations; driver regulators; heterogeneous graph transformer; hierarchical regulatory network; single-cell multi-omics

DOI:  https://doi.org/10.1093/bib/bbaf664
Nat Commun. 2026 Feb 03.

Boosting the detection of enhancer-promoter loops via normalization methods for chromatin interaction data.

Xiaotao Wang, Detong Shi, Feiyang Xue, Yunxia Liu, Hongbo Yang, Linghan Jiang.

Accurate detection of enhancer-promoter loops from genome-wide chromatin interaction data is critical for understanding gene regulation. Standard normalization methods, such as matrix balancing approaches, are widely used to correct biases in chromatin contact data prior to chromatin loop detection. However, while these methods preserve structural loop signals, they often attenuate enhancer-promoter interaction signals, making these regulatory loops more difficult to detect. To address this limitation, we develop Raichu, a normalization method for chromatin contact data. Raichu identifies nearly twice as many loops as conventional normalization approaches, recovering almost all previously detected loops while uncovering thousands of additional enhancer-promoter interactions that are otherwise missed. With its improved sensitivity for regulatory loops, Raichu detects more biologically meaningful differential interactions, including those between conditions within the same cell type. Moreover, Raichu performs robustly across a wide range of sequencing depths, resolutions, species, and experimental platforms, making it a versatile tool for revealing insights into three-dimensional genome organization and transcriptional regulation.

DOI: https://doi.org/10.1038/s41467-026-69082-z
Mol Syst Biol. 2026 Feb 02.

Differential nucleosome organization in human interphase and metaphase chromosomes.

Keren Li, Irem Unlu, Yiren Tu, Lilien N Voong, Yanyan Lu, Brody Kendall, Xiaotian Ma, Sin Lei Pui, Meng Tao, Ji-Ping Wang, Xiaozhong Wang.

  DNA bendability plays a critical role in stabilizing nucleosome assembly, yet its contribution to nucleosome dynamics in vivo remains poorly understood. Here, we applied chemical mapping to generate high-resolution nucleosome positioning maps at single-base-pair resolution from human interphase and metaphase chromosomes, revealing distinct patterns of nucleosome organization between the two states. Notably, we observed a unifying pattern of nucleosome positioning near euchromatic landmarks, including promoters, enhancers, and insulators, during mitosis. Interphase nucleosomes exhibited extensive repositioning, marked by increased nucleosome density, reduced spacing between nucleosomes, and the appearance of additional fragile nucleosomes compared to metaphase. Furthermore, our results show that metaphase nucleosomes display significantly higher DNA cyclizability around the dyad axis, whereas interphase nucleosomes, particularly those near regulatory regions, tend to position DNA with greater cyclizability at the edges of the nucleosome. Together, these findings highlight a dynamic interplay between DNA mechanics and nucleosome organization during the cell cycle.

Keywords:  Chemical Mapping; Chromosome; DNA Cyclizability; Mitosis; Nucleosome

DOI:  https://doi.org/10.1038/s44320-026-00192-y
PLoS Comput Biol. 2026 Feb 03. 22(2): e1013932

BiCLUM: Bilateral contrastive learning for unpaired single-cell multi-omics integration.

Yin Guo, Izaskun Mallona, Mark D Robinson, Limin Li.

The integration of single-cell multi-omics data provides a powerful approach for understanding the complex interplay between different molecular modalities, such as RNA expression, chromatin accessibility and protein abundance, measured through assays like scRNA-seq, scATAC-seq and CITE-seq, at single-cell resolution. However, most existing single-cell technologies focus on individual modalities, limiting a comprehensive understanding of their interconnections. Integrating such diverse and often unpaired datasets remains a challenging task due to unknown cell correspondences across distinct feature spaces and limited insights into cell-type-specific activities in non-scRNA-seq modalities. In this work, we propose BiCLUM, a Bilateral Contrastive Learning approach for Unpaired single-cell Multi-omics integration, which simultaneously enforces cell-level and feature-level alignment across modalities. BiCLUM first transforms one modality, such as scATAC-seq, into the data space of another modality, such as scRNA-seq, using prior genomic knowledge. It then learns cell and gene embeddings simultaneously through a bilateral contrastive learning framework, incorporating both cell-level and feature-level contrastive losses. Across multiple RNA+ATAC and RNA+protein datasets, BiCLUM consistently outperforms or matches existing integration methods in both visualization and quantitative benchmarks. Importantly, BiCLUM embeddings preserve biologically meaningful regulatory relationships between chromatin accessibility and gene expression, as evidenced by significantly higher gene-peak correlations than random controls. Downstream analyses further demonstrate that BiCLUM-derived embeddings facilitate transcription factor activity inference, identification of cell-type-specific marker genes, functional enrichment, and cell-cell interaction mapping. Comprehensive hyperparameter sensitivity and ablation analyses further establish BiCLUM as a robust and interpretable framework that not only achieves effective cross-modal alignment but also retains the underlying regulatory and functional landscape across single-cell modalities.

DOI: https://doi.org/10.1371/journal.pcbi.1013932
Nucleic Acids Res. 2026 Feb 05. pii: gkag089. [Epub ahead of print]54(4):

Single-molecule tracking of DNMT1 in living cells reveals its cell cycle dynamics and its redistribution upon drug treatment.

Eliza S Lee, Ella R Tommer, Paul B Rothman, Sarah V Middleton, Daniel T Youmans, Thomas R Cech.

DNMT1 is a methyltransferase that restores 5-methylcytidine marks on newly replicated DNA and is required for maintaining epigenetic inheritance. Using Halo-tagged DNMT1 and highly inclined thin illumination (HiLo) microscopy, we show that DNMT1 mobility in living human cells changes under a variety of conditions. DNMT1 molecules become increasingly bound to chromatin in the S phase of the cell cycle, but surprisingly only ∼ 12% chromatin-bound DNMT1 is sufficient to maintain DNA methylation. Upon treatment with small molecule inhibitors, GSK-3484862 (GSK), 5-azacytidine (5-azaC) and decitabine (5-aza-deoxyC), in vivo DNMT1 dynamics are greatly altered. Unexpectedly, treatment of cells with GSK, a non-covalent inhibitor, causes binding of DNMT1 to chromatin similar to that observed upon treatment with 5-azaC and decitabine, covalent inhibitors. 5-azaC inhibition of DNMT1 dynamics occurs during the S phase of the cell cycle. Unexpectedly, mutations in the disordered, Asp- and Glu-rich N-terminal region of DNMT1 dramatically decrease its mobility and increase chromatin binding. Collectively, our work using live cell single molecule imaging quantifies the molecular dynamics of DNMT1 and how this relates to its function under physiological conditions and upon drug treatment. Understanding the dynamics of DNMT1 in vivo provides a framework for developing better therapeutics that target DNMT1.

DOI: https://doi.org/10.1093/nar/gkag089