bims-crepig 2025-10-19 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2025–10–19
six papers selected by
Connor Rogerson, University of Cambridge

scTFBridge: a disentangled deep generative model informed by TF-motif binding for gene regulation inference in single-cell multi-omics.
Characterization of induced cohesin loop extrusion trajectories in living cells.
Using single-cell perturbation screens to decode the regulatory architecture of splicing factor programs.
Dynamics of microcompartment formation at the mitosis-to-G1 transition.
Predictive prioritization of enhancers associated with pancreatic disease risk.
Loss of BPTF restores estrogen response and suppresses metastasis of mammary tumors.

Nat Commun. 2025 Oct 15. 16(1): 9166

scTFBridge: a disentangled deep generative model informed by TF-motif binding for gene regulation inference in single-cell multi-omics.

Feng-Ao Wang, Chenxin Yi, Jiajun Chen, Ruikun He, Junwei Liu, Yixue Li.

The interplay between transcription factors (TFs) and regulatory elements (REs) drives gene transcription, forming gene regulatory networks (GRNs). Advances in single-cell technologies now enable simultaneous measurement of RNA expression and chromatin accessibility, offering unprecedented opportunities for GRN inference at single-cell resolution. However, heterogeneity across omics layers complicates regulatory feature extraction. We present scTFBridge, a multi-omics deep generative model for GRN inference. scTFBridge disentangles latent spaces into shared and specific components across omics layers. By integrating TF-motif binding knowledge, scTFBridge aligns shared embeddings with specific TF regulatory activities, enhancing biological interpretability. Using explainability methods, scTFBridge computes regulatory scores for REs and TFs, enabling robust GRN inference. Our results further demonstrate that scTFBridge can identify cell-type-specific susceptibility genes and distinct regulatory programs, providing insights into gene regulation mechanisms at the single-cell level.

DOI: https://doi.org/10.1038/s41467-025-64227-y
Nat Genet. 2025 Oct 16.

Characterization of induced cohesin loop extrusion trajectories in living cells.

Ruiqi Han, Yike Huang, Michelle J Robers, Mikhail Magnitov, Iwan Vaandrager, Amin Allahyar, Marjon J A M Verstegen, Kexin Zhang, Elzo de Wit, Wouter de Laat, Peter H L Krijger.

Cohesin (SMC1-SMC3-RAD21) constantly extrudes DNA loops to organize chromosomes into structural domains, pausing and anchoring at specific DNA-bound CTCF molecules. To study the detailed consequences of cohesin loop extrusion, we developed TArgeted Cohesin Loader (TACL) for controlled pan-cellular activation of chromatin loop formation at defined genomic locations in living cells. With TACL, we show that highly complex looping networks can exist, with extruding cohesin complexes that block each other, drive cohesin queuing and induce loop anchoring at nearly all CTCF-bound sites. TACL loops extend upon acute depletion of STAG2, PDS5A or WAPL. Activated cohesin loop extrusion hinders local gene transcription and can alter chromatin accessibility and H3K27ac distribution. TACL shows that the loading/extrusion complex NIPBL-MAU2 can be transported by cohesin to CTCF sites but, together with SMC1, to enhancers in a RAD21-independent manner. TACL thus enables studying the consequences of activated loop extrusion at defined genomic locations.

DOI: https://doi.org/10.1038/s41588-025-02358-0
Nucleic Acids Res. 2025 Oct 14. pii: gkaf855. [Epub ahead of print]53(19):

Using single-cell perturbation screens to decode the regulatory architecture of splicing factor programs.

Miquel Anglada-Girotto, Samuel Miravet-Verde, Luis Serrano.

Splicing factors shape the isoform pool of most transcribed genes, playing a critical role in cellular physiology. Their dysregulation is a hallmark of diseases like cancer, where aberrant splicing contributes to progression. While exon inclusion signatures accurately assess changes in splicing factor activity, systematically mapping disease-driver regulatory interactions at large scale remains challenging. Perturb-seq, which combines CRISPR-based perturbations with single-cell RNA sequencing, enables high-throughput measurement of perturbed gene expression signatures but lacks exon-level resolution, limiting its application for splicing factor activity analysis. Here, we show that shallow artificial neural networks can estimate splicing factor activity from gene expression signatures, bypassing the need for exon-level data. As a case study, we map the genetic interactions regulating splicing factors during carcinogenesis, using the shift in splicing program activity-where oncogenic-like splicing factors become more active than tumor suppressor-like factors-as a molecular reporter of a Perturb-seq screen. Our analysis reveals a cross-regulatory network among splicing factors, involving protein-protein and splicing-mediated interactions, with MYC and additional candidate pathways linking cancer driver mutations to splicing regulation. This regulation recapitulates splicing program dynamics during development. Altogether, we establish a versatile framework for studying splicing factor regulation and demonstrate its utility for uncovering disease mechanisms.

DOI: https://doi.org/10.1093/nar/gkaf855
Nat Struct Mol Biol. 2025 Oct 17.

Dynamics of microcompartment formation at the mitosis-to-G1 transition.

Viraat Y Goel, Nicholas G Aboreden, James M Jusuf, Haoyue Zhang, Luisa P Mori, Leonid A Mirny, Gerd A Blobel, Edward J Banigan, Anders S Hansen.

As cells exit mitosis and enter G1, chromosomes decompact and transcription is reestablished. Hi-C studies have indicated that all interphase three-dimensional genome features, including A/B compartments, topologically associating domains and CCCTC-binding factor loops, are lost during mitosis. However, Hi-C is insensitive to features such as microcompartments, nested focal interactions between cis-regulatory elements. Here we apply region capture Micro-C to mouse erythroblasts from mitosis to G1. We unexpectedly observe microcompartments in prometaphase, which strengthen in anaphase and telophase before weakening throughout G1. Microcompartment anchors coincide with transcriptionally spiking promoters during mitosis. Loss of condensin loop extrusion differentially impacts microcompartments and A/B compartments, suggesting that they are partially distinct. Polymer modeling shows that microcompartment formation is favored by chromatin compaction and disfavored by loop extrusion, providing a basis for strong microcompartmentalization in anaphase and telophase. Our results suggest that compaction and homotypic affinity drive microcompartment formation, which may explain transient transcriptional spiking at mitotic exit.

DOI: https://doi.org/10.1038/s41594-025-01687-2
Cell Genom. 2025 Oct 16. pii: S2666-979X(25)00296-4. [Epub ahead of print] 101040

Predictive prioritization of enhancers associated with pancreatic disease risk.

Pancreatic Cancer Cohort Consortium

  Genetic and epigenetic variation in enhancers is associated with disease susceptibility; however, linking enhancers to target genes and predicting enhancer dysfunction remain challenging. We mapped enhancer-promoter interactions in human pancreas using 3D chromatin assays across 28 donors and five cell types. Using a network approach, we parsed these interactions into enhancer-promoter tree models, enabling quantitative, genome-wide analysis of enhancer connectivity. A machine learning algorithm built on these trees estimated enhancer contributions to cell-type-specific gene expression. To test predictions, we perturbed enhancers in primary human pancreas cells with CRISPR interference and quantified effects at single-cell resolution using RNA fluorescence in situ hybridization (FISH) and high-throughput imaging. Tree models also annotated germline risk variants linked to pancreatic disorders, connecting them to candidate target genes. For pancreatic ductal adenocarcinoma risk, acinar regulatory elements showed greater variant enrichment, challenging the ductal cell-of-origin view. Together, these datasets and models provide a resource for studying pancreatic disease genetics.

Keywords:  3D genome organization; CRISPR; GWAS; cell identity; diabetes; enhancer; graph models; noncoding variants; pancreas; pancreatic cancer

DOI:  https://doi.org/10.1016/j.xgen.2025.101040
Nat Commun. 2025 Oct 15. 16(1): 9168

Loss of BPTF restores estrogen response and suppresses metastasis of mammary tumors.

Michael F Ciccone, Dhivyaa Anandan, Deeptiman Chatterjee, Chen Chen, Marygrace C Trousdell, Rebecca Anderson, Steven M Lewis, Mackenzie K Callaway, Chris Z Zhao, Amritha Varshini Hanasoge Somasundara, Suzanne Russo, Shih-Ting Yang, Yixin Zhao, Julie Ostrander, John E Wilkinson, William C K Pomerantz, Adam Siepel, David L Spector, Jessica Tollkuhn, Camila O Dos Santos.

Context-specific epigenetic dependencies, shaped by chromatin remodeling can create exploitable vulnerabilities for cancer therapies that are unique to tissue types and cellular identities. Here, we show that loss of BPTF (Bromodomain PHD Finger Transcription Factor), a core component of the NURF (Nucleosome Remodeling Factor) complex, results in the emergence of estrogen-responsive, tamoxifen-sensitive, Estrogen Receptor alpha (ERα) positive mammary tumors without altering cancer cell state and tumor pathology. Elevated ERα levels in BPTFKO mammary tumor cells are linked with decreased TGF-β activity and limited metastatic spread of mammary tumor cells to the lungs. Loss of ERα is sufficient to restore TGF-β activity and the metastatic potential in BPTFKO tumors. These findings highlight a mechanism through which BPTF regulates tumor development and progression in mammary epithelial cells, offering insights into the interplay between chromatin remodeling, estrogen signaling, and their resultant adjuvant therapeutic potential in breast cancer.

DOI: https://doi.org/10.1038/s41467-025-64255-8