bims-crepig 2025-12-28 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2025–12–28
nine papers selected by
Connor Rogerson, University of Cambridge

Antisense transcription can induce expression memory via stable promoter repression.
Designing synthetic regulatory elements using the generative AI framework DNA-Diffusion.
Decoding cnidarian cell type gene regulation.
H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations.
Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling.
Towards personalized epigenomics: learning shared chromatin landscapes and joint de-noising of histone modification assays.
Two distinct chromatin modules regulate proinflammatory gene expression.
Molecular basis of NFIB-mediated regulation of oncogenic transcription.
Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm.

Genome Biol. 2025 Dec 20. 26(1): 430

Antisense transcription can induce expression memory via stable promoter repression.

Verena Mutzel, Till Schwämmle, Svearike Oeverdieck, Lucija Librenjak, Benedikt Boesen, Melissa Bothe, Rutger A F Gjaltema, Ilona Dunkel, Gemma Noviello, Edda G Schulz.

   BACKGROUND: The capacity of cells to retain a memory of previous signals enables acquisition of unique fates and adaptation to their environment. The underlying gene expression memory can arise from mutual repression of two genes, forming a toggle switch. Mutual repression can occur at antisense loci, where convergent genes repress each other in cis. The conditions for generating expression memory via antisense transcription remain poorly understood. To address this question, we combine mathematical modeling, genomics and a synthetic biology approach.
RESULTS: Simulations demonstrate stable memory emergence when both genes in an antisense pair transcribe via the convergent promoter and induce a stable repressive chromatin state. Genome-wide analysis of nascent transcription supports antisense-mediated promoter repression, since promoter-overlapping antisense gene pairs exhibit mutually exclusive expression. Through constructing a synthetic antisense locus in mESCs, we demonstrate that antisense transcription can induce stable repression, a key prerequisite for memory. Repression stability increases during mESC differentiation, highlighting cell type-specific epigenetic memory.
CONCLUSIONS: Our work establishes a quantitative framework which predicts that antisense-mediated cis-memory can arise within physiologically relevant conditions, and shows that a biological phenomenon with kinetics in the range of weeks can emerge from the interplay of multiple faster molecular processes. This framework, combined with our experimental findings, demonstrates how antisense transcription can encode stable gene expression states. Our discovery that stem cells adjust their memory capacity during differentiation may clarify mechanisms underlying stemness maintenance.

Keywords:  Antisense transcription; Embryonic stem cells; Epigenetics; Mathematical modelling; Synthetic genomics; Systems biology; Transcriptional regulation

DOI:  https://doi.org/10.1186/s13059-025-03875-1
Nat Genet. 2025 Dec 23.

Designing synthetic regulatory elements using the generative AI framework DNA-Diffusion.

Lucas Ferreira DaSilva, Simon Senan, Judith F Kribelbauer-Swietek, Zain Munir Patel, Lithin Karmel Louis, Aniketh Janardhan Reddy, Sameer Gabbita, Jonathan D Rosen, Zach Nussbaum, César Miguel Valdez Córdova, Aaron Wenteler, Noah Weber, Tin M Tunjic, Martino Mansoldo, Talha Ahmad Khan, Gue-Ho Hwang, Vincent Gardeux, David T Humphreys, Cameron Smith, Matei Bejan, Peter Bromley, Will Connell, Bart Deplancke, Michael I Love, Emily S Wong, Wouter Meuleman, Luca Pinello.

Systematically designing regulatory elements for precise gene expression control remains a central challenge in genomics and synthetic biology. Here we introduce DNA-Diffusion, a generative artificial intelligence framework that uses machine learning trained on DNA accessibility data from diverse cell lines to design compact regulatory elements with cell-type-specific activity. We show that DNA-Diffusion generates 200-base-pair synthetic elements that recapitulate endogenous transcription factor binding grammar while exhibiting enhanced cell-type specificity. We validated these elements using a 5,850-element STARR-seq library across three cell lines. Moreover, we demonstrated successful endogenous gene modulation using EXTRA-seq, reactivating AXIN2, a leukemia-protective gene, in its native genomic context. Our approach outperforms existing computational methods in balancing functional activity with cell-type specificity while maintaining sequence diversity. This work establishes DNA-Diffusion as a powerful tool for engineering compact, highly specific regulatory elements crucial for advancing gene therapies and understanding gene regulation.

DOI: https://doi.org/10.1038/s41588-025-02441-6
Nat Ecol Evol. 2025 Dec 22.

Decoding cnidarian cell type gene regulation.

Anamaria Elek, Marta Iglesias, Lukas Mahieu, Grygoriy Zolotarov, Xavier Grau-Bové, Stein Aerts, Arnau Sebé-Pedrós.

Animal cell types are defined by differential access to genomic information-a process orchestrated by the combinatorial activity of transcription factors that bind to cis-regulatory elements (CREs) to control gene expression. Changes in these gene regulatory networks (GRNs) underlie the origin and diversification of cell types, yet the regulatory logic and specific GRNs that define cell identities remain poorly resolved across the animal tree of life. Cnidarians, as early-branching metazoans, provide a critical window into the early evolution of cell type-specific genome regulation. Here we profiled chromatin accessibility in 60,000 cells from whole adults and gastrula-stage embryos of the sea anemone Nematostella vectensis. We identified 112,728 putative CREs and quantified their activity across cell types, revealing pervasive combinatorial enhancer usage and distinct promoter architectures. To decode the underlying regulatory grammar, we trained sequence-based models predicting CRE accessibility and used these models to infer cell type similarities that reflect known ontogenetic relationships. By integrating sequence motifs, transcription factor expression and CRE accessibility, we reconstructed the GRNs that define cnidarian cell types. Our results show the regulatory complexity underlying cell differentiation in a morphologically simple animal and highlight conserved principles in animal gene regulation. This work provides a foundation for comparative regulatory genomics to understand the evolutionary emergence of animal cell type diversity.

DOI: https://doi.org/10.1038/s41559-025-02906-1
Mol Cell. 2025 Dec 19. pii: S1097-2765(25)00971-2. [Epub ahead of print]

H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations.

Sandra Nitsch, Aria E Coraor, Tamas Schauer, Yiheng Wu, Jianfeng Sun, Natalie Möritz, Jonas Funke, Harsh Nagpal, Gabriella N L Chua, Federica Battistini, Shannon M Lauberth, Eva Richard, Modesto Orozco, Shixin Liu, Lourdes R Desviat, Beat Fierz, Hendrik Dietz, Robert G Roeder, Juan J de Pablo, Robert Schneider.

  Histone modifications play crucial roles in genome function. However, how chromatin integrates physiological and metabolic responses at the molecular level remains largely unknown. Acetylation of histone H4 lysine 16 (H4K16ac) is unique, as it directly regulates chromatin architecture. Here, we investigated the roles of two additional H4K16 short-chain acylations, propionylation (H4K16pr) and butyrylation (H4K16bu), in chromatin architecture and transcriptional regulation. We demonstrate distinct in vitro effects of H4K16 acylations on chromatin structure, including inter- and intra-nucleosomal interactions. Utilizing a mouse model of the metabolic disease propionic acidemia, we reveal a transcriptional response concomitant with changes in H4K16 acylations in vivo. Our work suggests the importance of simultaneous action of histone acylations for transcriptional robustness through effects on nucleosomal interactions. We propose that this mode of action distinguishes H4K16 acylations from other modifications that also differ by one carbon, such as methylations.

Keywords:  H4K16 acylations; chromatin dynamics; metabolic challenge

DOI:  https://doi.org/10.1016/j.molcel.2025.11.030
Cell Rep. 2025 Dec 19. pii: S2211-1247(25)01466-4. [Epub ahead of print]45(1): 116694

Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling.

Emily R Feierman, Alekh Paranjapye, Annabel K Sangree, Rili Ahmad, Marissa J Maroni, Qi Qiu, Kyuhyun Choi, Marc Fuccillo, Hao Wu, Erica Korb.

  Neuronal responses to stimuli rely on transcriptional programs controlled by histone proteins, including histone variants. Recent findings demonstrate that the variant H2BE promotes transcription and is critical for long-term memory, which relies on intact activity-dependent responses. However, whether H2BE is regulated by synaptic stimuli and controls activity-dependent responses remains to be determined. Here, we demonstrate that, unlike other variants, H2BE is depleted following long-term but not short-term increases in activity, indicating that its loss may promote homeostatic downscaling. Neurons lacking H2BE are unable to mount proper long-term activity-dependent transcriptional responses both in cultured neurons and in animal models. Lastly, we demonstrate that H2BE-knockout neurons fail to undergo the electrophysiological changes associated with homeostatic plasticity. In summary, these data demonstrate that H2BE expression is inversely correlated with activity and is necessary for long-term activity-dependent scaling responses, revealing a mechanism through which histone variants control homeostatic plasticity in neurons.

Keywords:  CP: molecular biology; CP: neuroscience; H2B; H2B2E; H2BC21; H2BE; activity-dependent transcription; histone; histone variant; homeostatic scaling

DOI:  https://doi.org/10.1016/j.celrep.2025.116694
NAR Genom Bioinform. 2025 Dec;7(4): lqaf188

Towards personalized epigenomics: learning shared chromatin landscapes and joint de-noising of histone modification assays.

Tanmayee Narendra, Giovanni Visonà, Crhistian de Jesus Cardona, James Abbott, Gabriele Schweikert.

Epigenetic mechanisms enable cellular differentiation and the maintenance of distinct cell types. They enable rapid responses to external signals through changes in gene regulation and their registration over longer time spans. Consequently, the chromatin landscape, which is the overall organization and biochemical state of chromatin, exhibits both cell-type and individual specificity and contributes to phenotypic diversity. Genomic distributions of chromatin features are typically measured using chromatin immunoprecipitation sequencing and related methods. However, these measurements are subject to substantial biases introduced by the chromatin landscape itself. Here, we introduce DecoDen, which uses measurements of several different histone modifications, to simultaneously learn shared chromatin landscapes while de-biasing individual measurement tracks. We demonstrate DecoDen's effectiveness on an integrative analysis of histone modification patterns across multiple tissues in personal epigenomes. DecoDen is available at https://github.com/ntanmayee/decoden.

DOI: https://doi.org/10.1093/nargab/lqaf188
Nat Cell Biol. 2025 Dec 24.

Two distinct chromatin modules regulate proinflammatory gene expression.

Isabelle Seufert, Irene Gerosa, Vassiliki Varamogianni-Mamatsi, Anastasiya Vladimirova, Ezgi Sen, Stefanie Mantz, Anne Rademacher, Sabrina Schumacher, Panagiotis Liakopoulos, Petros Kolovos, Simon Anders, Jan-Philipp Mallm, Argyris Papantonis, Karsten Rippe.

Gene activation and coregulation have been attributed to different mechanisms, such as enhancer-promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However, genome-wide studies exploring mechanistic differences in endogenous gene regulation in primary human cells are scarce. Here we dissect the proinflammatory gene expression programme induced by tumor necrosis factor (TNF) in human endothelial cells using sequencing- and imaging-based methods. Our findings, enabled by the co-accessibility analysis of deep-coverage single-cell chromatin accessibility data with our RWireX software, identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. The TNF-dependent induction timing and strength as well as changes in transcriptional bursting kinetics differed for genes in the AC and DC modules, pointing to functionally distinct regulatory mechanisms. These findings provide a framework for understanding how cells achieve rapid and precise control of gene expression.

DOI: https://doi.org/10.1038/s41556-025-01819-2
Nucleic Acids Res. 2025 Nov 26. pii: gkaf1369. [Epub ahead of print]53(22):

Molecular basis of NFIB-mediated regulation of oncogenic transcription.

Ci Zhu, Ding Xiao, Yueyu Wang, Hong Han, Chengxiao Qin, Shuang Liu, Xi Chen, Hejin Xiao, Xin Chen, Junfeng Shi, Juyu Tang, Jie Shen, He Song.

The Nuclear Factor I (NFI) family of transcription factors orchestrates key regulatory programs in development, differentiation, and metabolism, with dysregulation implicated in diverse pathological conditions, including cancer. Among the paralogs, NFIB has emerged as an oncogenic driver in multiple tumor types, yet the mechanisms through which it engages DNA and directs oncogenic transcriptional programs remain undefined. Here, using cancer cells with high NFIB expression, we demonstrate that NFIB promotes malignant phenotypes, as CRISPR-Cas9 knockout impairs proliferation, migration, and invasion. Transcriptomic profiling reveals that NFIB regulates a cancer-enriched gene network that includes FGFR3 and PDGFRB. Biophysical analyses show that NFIB, including its DNA-binding domain, functions as a monomer and binds DNA with strict 1:1 stoichiometry. High-resolution crystal structures of NFIB DNA-binding domain bound to ChIP-seq-derived DNA motifs reveal a monomeric binding mode mediated by conserved base-specific interactions with the TGGCA sequence, providing an atomic view of NFIB-DNA recognition. Mutational disruption of key DNA-contacting residues abolishes DNA binding and transcriptional activation, linking atomic-level recognition to oncogenic transcriptional regulation. Together, these findings elucidate the structural mechanism underlying NFIB function in cancer and establish a framework for therapeutic strategies targeting NFIB-driven malignancies.

DOI: https://doi.org/10.1093/nar/gkaf1369
Nat Cell Biol. 2025 Dec 22.

Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm.

Allana Schooley, Sergey V Venev, Vasilisa Aksenova, Jesse W Lehman, Emily Navarrete, Athma A Pai, Mary Dasso, Job Dekker.

Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis.

DOI: https://doi.org/10.1038/s41556-025-01828-1