bims-crepig 2025-11-16 papers

Issue of 2025–11–16
five papers selected by
Connor Rogerson, University of Cambridge

NAR Cancer. 2025 Dec;7(4): zcaf039

Transcriptional pause release at enhancers mediates cell identity.

This short review highlights recent findings related to transcription factor-mediated RNA polymerase II (Pol II) pause release at enhancers and its role in regulating cell identity. We discuss how the transcriptional state of Pol II, either paused or released, shapes enhancer-promoter interactions, thereby influencing gene expression programs that define cell identity. We further summarize current knowledge of DNA-binding transcription factors that regulate Pol II pause release at enhancers and explore how this process influences cell identity. We propose a novel concept of therapy-induced molecular amnesia, where temporary inhibition of enhancer-proximal Pol II pause release and enhancer RNA transcription affects enhancer-promoter interactions differently in distinct cellular contexts. In some contexts, preservation of enhancer-promoter interactions allows rapid transcriptional reactivation and maintenance of cell identity upon recovery. In other contexts, repeated inhibition of enhancer RNA transcription leads to the permanent dissociation of enhancer-promoter interactions and loss of cell identity. Our model suggests that manipulating Pol II pause release at enhancers could selectively reverse certain aggressive tumor cell identities, limit tumor cell plasticity, and improve therapy responsiveness.

DOI: https://doi.org/10.1093/narcan/zcaf039

Nat Cell Biol. 2025 Nov 11.

Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation.

Xukun Lu, Lijuan Wang, Bofeng Liu, Xiaoyu Hu, Zhengmao Wang, Ling Liu, Guang Yu, Lijun Dong, Feng Kong, Qiang Fan, Yu Zhang, Wei Xie.

In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a 'leaky' H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment.

DOI: https://doi.org/10.1038/s41556-025-01805-8

Genes Dev. 2025 Nov 10.

SOX2 phosphorylation during mitosis limits genomic damage.

Charles A C Williams, Dounia Djeghloul, Nicolas Veland, Alhafidz Hamdan, Maria Kalantzaki, Erika Lo, Robert Illingworth, Alex Von Kriegsheim, Amanda G Fisher, Abdenour Soufi, Steven M Pollard.

Pioneer transcription factors (TFs) such as SOX2 play critical roles in the control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs) and is typically highly expressed in glioblastoma stem cells (GSCs), where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation during NSC division and identified an unexpected role for excessive SOX2 pioneer activity in driving mitotic damage. We found that SOX2 phosphorylation during mitosis is a key switch that prevents promiscuous chromatin binding across the genome. Without this regulatory control, excessive SOX2 in mitosis triggers chromatin opening, resulting in increased mitotic transit times and increased chromosomal damage. Therefore, elevated levels of SOX2 in cancers may have dual oncogenic roles: inducing stemness during interphase via its well-known transcriptional roles but simultaneously promoting chromosomal disruptions through unconstrained pioneer factor activity.

Keywords: DNA damage; SOX2; heterochromatin; mitosis; mitotic bookmarking; neural stem cell; phosphorylation; transcription

DOI: https://doi.org/10.1101/gad.352664.125

Nat Genet. 2025 Nov 14.

Uniform dynamics of cohesin-mediated loop extrusion in living human cells.

Thomas Sabaté, Benoît Lelandais, Marie-Cécile Robert, Michael Szalay, Jean-Yves Tinevez, Edouard Bertrand, Christophe Zimmer.

Most animal genomes are partitioned into topologically associating domains (TADs), created by cohesin-mediated loop extrusion and defined by convergently oriented CCCTC-binding factor (CTCF) sites. The dynamics of loop extrusion and its regulation remain poorly characterized in vivo. Here we tracked the motion of TAD anchors in living human cells to visualize and quantify cohesin-dependent loop extrusion across multiple endogenous genomic regions. We show that TADs are dynamic structures whose anchors are brought in proximity about once per hour and for 6-19 min (~16% of the time). Moreover, TADs are continuously extruded by multiple cohesin complexes. Remarkably, despite strong differences in Hi-C patterns across chromatin regions, their dynamics is consistent with the same density, residence time and speed of cohesin. Our results suggest that TAD dynamics is primarily governed by the location and affinity of CTCF sites, enabling genome-wide predictive models of cohesin-dependent chromatin interactions.

DOI: https://doi.org/10.1038/s41588-025-02406-9

Cell. 2025 Nov 12. pii: S0092-8674(25)01191-2. [Epub ahead of print]

Molecular grammars of predicted intrinsically disordered regions that span the human proteome.

Kiersten M Ruff, Matthew R King, Alexander W Ying, Vicky Liu, Avnika Pant, Whitney E Lieberman, Min Kyung Shinn, Xiaolei Su, Cigall Kadoch, Rohit V Pappu.

Intrinsically disordered regions (IDRs) of proteins are defined by molecular grammars. This refers to IDR-specific non-random amino acid compositions and non-random patterning of distinct pairs of amino acid types. Here, we introduce grammars inferred using NARDINI+ (GIN) as a resource that uncovers IDR-specific and IDRome-spanning grammars. Using GIN-enabled analyses, we find that specific IDR features and GIN clusters are associated with distinct biological processes, intra-cellular localization preferences, specialized molecular functions, and functionalization as assessed by cellular fitness correlations. IDRs with exceptional grammars, defined as sequences with high-scoring non-random features, are harbored in proteins and complexes that enable spatial and temporal sorting of biochemical activities within the nucleus. Overall, GIN can be used to extract sequence-function relationships of individual IDRs or clusters of IDRs, to redesign extant IDRs or design de novo IDRs, to perform evolutionary analyses through the lens of molecular grammars and GIN clusters, and to make sense of IDR-specific disease-associated mutations.

Keywords: RNA polymerase; biomolecular condensates; cancer; intrinsically disordered regions; molecular grammars; subcellular localization; transcriptional regulation

DOI: https://doi.org/10.1016/j.cell.2025.10.019