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PubMed2026

Nuclear speckles: a fundamental layer of gene regulation.

Within the cell nucleus, non-DNA structures called nuclear bodies interact with chromatin to regulate gene expression and organize our genetic material. Among nuclear bodies, nuclear speckles are prominent. They interact with broad genomic regions, serve as major gene-activating structures, and are implicated in viral infection, cancer, neurodegeneration, stress response, and development. Advances that integrate genomics with imaging are leading to a deeper understanding of how nuclear speckles fit into our current knowledge of chromatin biology, genome organization, and the central dogma of biology. Collectively, these recent studies emphasize nuclear speckles as key gene regulatory structures within the cell nucleus, offering new perspectives on how gene expression dysregulation is linked to disease.

Humans↗
PubMed2025

Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with the nuclear speckle.

Viruses rely on host cellular machinery for replication. After entering the nucleus, the HIV genome accumulates in nuclear niches where it undergoes reverse transcription and integrates into neighboring chromatin, promoting high transcription rates and new virus progeny. Despite antiretroviral treatment, viral genomes can persist in these nuclear niches and reactivate upon treatment interruption, raising the possibility that they could play a role in the establishment of viral reservoirs. The post-nuclear entry dynamics of HIV remain unclear, and understanding these steps is critical for revealing how viral reservoirs are established. In this study, we elucidate the formation of HIV-induced CPSF6 puncta and the domains of CPSF6 essential for this process. We also explore the roles of nuclear speckle scaffold factors, SON and SRRM2, in the biogenesis of these puncta. Through genetic manipulation and depletion experiments, we demonstrate the key role of the intrinsically disordered region of SRRM2 in enlarging nuclear speckles in the presence of the HIV capsid. We identify the FG domain of CPSF6 as essential for both puncta formation and binding to the viral core, which serves as the scaffold for CPSF6 puncta. While the low-complexity regions (LCRs) modulate CPSF6 binding to the viral capsid, they do not contribute to puncta formation, nor do the disordered mixed charge domains (MCDs) of CPSF6. Interestingly, the FG peptide facilitates viral replication. These results demonstrate how HIV evolved to hijack host nuclear factors, enabling its persistence in the host. Of note, this study provides new insights into the underlying interactions between host factors and viral components, advancing our understanding of HIV nuclear dynamics and offering potential therapeutic targets for preventing viral persistence.

Journal Article↗
PubMed2026

Acidic transcription factors position the genome at nuclear speckles through transcription-dependent and -independent mechanisms.

A small fraction of the genome reproducibly positions near nuclear speckles (NSs), increasing the expression and/or splicing efficiency of NS-associated genes. How specific genomic regions in mammalian cells are targeted to NSs remains unclear. Here, we demonstrate the establishment of genome-wide NS association without active transcription. We show that DNA sequences derived from NS-associated regions, when integrated as transgenes, are autonomously targeted to NSs. By systematically dissecting one such genomic locus, the COL1A1-SGCA locus, we identified redundant NS-targeting cis-regulatory elements, including an ∼600-bp fragment with 17 binding motifs for 8 transcription factors (TFs). Four NS-targeting TFs within this fragment contain acidic activation domains (AADs) that provide both chromatin-context and transcription-dependent NS targeting, properties that appear to be common among several other tested AADs. A subset of acidic activator TFs contains an additional, transcription-independent NS-targeting activity. Our findings establish diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at the NS periphery for context-specific transcriptional responses.

Transcription, Genetic↗
PubMed2026

The periphery of nuclear speckles defines a spatially and temporally regulated compartment of long-lived intron-retained RNAs that resolves during mitosis.

RNA localization adds a fundamental layer to gene expression by determining when and where translation-ready mRNAs become available, yet how this timing is coordinated with nuclear architecture and cell-cycle progression remains unclear. Here we identify a subnuclear RNA niche at the nuclear speckle periphery that couples intron retention to cell-cycle-timed RNA release. Using compartment-resolved transcriptional inhibition, sequence-based deep learning and single-molecule and super-resolution RNA imaging in human pluripotent stem cells, we define a class of nuclear RNAs with long-lived retained introns that persist for hours and are enriched in transcripts encoding regulators of genome maintenance and mitosis, including centromere and kinetochore assembly, DNA repair and telomere maintenance. Long-lived retained introns exhibit elevated GC content, predicted structural stability and enrichment for nuclear speckle-associated RNA-binding proteins. In interphase, these RNAs localize to a distinct nuclear speckle-peripheral RNA niche in a spatial arrangement conserved across cell types. During mitotic remodelling, they undergo coordinated, kinase-dependent splicing and are released into the cytoplasm of early G1 daughter cells. Together, these findings link cis-encoded intronic features, subnuclear organization and mitotic remodelling to temporal control of RNA fate.

Mitosis↗
PubMed2026

Nuclear body assembly by a viral repeat RNA promotes Kaposi's sarcoma-associated herpesvirus gene expression.

Kaposin is the most abundantly expressed viral RNA in tumors caused by the oncogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV); however, its role in viral replication is not understood. Here, we show that kaposin, previously viewed as a protein-coding transcript, exists primarily as a nuclear viral long non-coding RNA (lncRNA) that rebuilds cellular nuclear speckles (NSs) adjacent to the viral genome to enhance viral gene expression. Kaposin is both necessary and sufficient to drive substantial NS remodeling, and this effect depends on repetitive elements within the RNA. Absence of kaposin-mediated NS remodeling, depletion of the essential NS protein, serine/arginine repetitive matrix 2 (SRRM2), or steric blocking of the kaposin repetitive elements impair viral gene expression. This work defines kaposin as a viral architectural RNA that drives nuclear speckle seeding beside the viral genome and reframes our understanding of lncRNA function and the spatial organization of transcription in the infected cell nucleus.

Kaposi's sarcoma-associated herpesvirus↗
PubMed2023

Mega-Enhancer Bodies Organize Neuronal Long Genes in the Cerebellum.

Dynamic regulation of gene expression plays a key role in establishing the diverse neuronal cell types in the brain. Recent findings in genome biology suggest that three-dimensional (3D) genome organization has important, but mechanistically poorly understood functions in gene transcription. Beyond local genomic interactions between promoters and enhancers, we find that cerebellar granule neurons undergoing differentiation in vivo exhibit striking increases in long-distance genomic interactions between transcriptionally active genomic loci, which are separated by tens of megabases within a chromosome or located on different chromosomes. Among these interactions, we identify a nuclear subcompartment enriched for near-megabase long enhancers and their associated neuronal long genes encoding synaptic or signaling proteins. Neuronal long genes are differentially recruited to this enhancer-dense subcompartment to help shape the transcriptional identities of granule neuron subtypes in the cerebellum. SPRITE analyses of higher-order genomic interactions, together with IGM-based 3D genome modeling and imaging approaches, reveal that the enhancer-dense subcompartment forms prominent nuclear structures, which we term mega-enhancer bodies. These novel nuclear bodies reside in the nuclear periphery, away from other transcriptionally active structures, including nuclear speckles located in the nuclear interior. Together, our findings define additional layers of higher-order 3D genome organization closely linked to neuronal maturation and identity in the brain.

Journal Article↗
PubMed2026

Centromeres and telomeres as rheological probes of the human cell nucleus.

The human genome contains genetic information essential for life, controlling all cellular processes via the central dogma of biology. It is a canonical example of a living polymer, yet the physical principles underlying its dynamical self-organization in the cell nucleus remain unknown. In this work, we investigate the polymeric nature of the genome in live human cells, by studying motions of the centers and free ends of linear chromosome polymers-the centromeres and telomeres-and rheology of their nuclear environment. Our findings reveal that telomeres have 10-times larger displacements than centromeres, exceeding by far predictions of polymer theories. We find that this unexpectedly large difference arises due to centromere and telomere localization in unique nuclear environments, distinct in both their biological activity and material rheology. While the former resides in the genome's silenced parts, the latter localizes in its transcriptionally active parts. Our rheological analysis shows that centromeres are embedded in an elastic environment, whereas telomeres' surroundings are viscous, directly affecting timescales and length scales of their respective motions. Our results suggest a key role of nuclear heterogeneity in genome dynamics, which we corroborate by biochemical perturbations of nuclear structures such as heterochromatin and nuclear speckles. Finally, upon homogenizing the nuclear environment by a hypoosmotic shock, we observe equal centromeric and telomeric motions, confirming our hypothesis. Our observations show that the heterogeneity of nuclear environment directly impacts timescales and length scales of local genomic motions, which may affect the spatiotemporal gene regulation across the cell nucleus.

Humans↗
PubMed2025

Nuclear-lamin-guided plastic positioning and folding of the human genome.

The human genome exhibits a highly ordered hierarchical architecture, yet the mechanisms governing its large-scale organization remain poorly understood. Here, we generate lamin single-, double-, and triple-knockout human embryonic and mesenchymal stem cells (hESCs and hMSCs) to investigate the role of lamins in the spatial organization of the human genome. Complete lamin depletion in hMSCs triggers extensive genome repositioning, disrupts chromosome territories, and dissolves long-range compartment clustering and mega-loops. Lamin loss affects both the nuclear periphery and interior, causing partial inversion and dispersion of nuclear speckles, accompanied by reduced global transcription and impaired stem cell homeostasis. Re-expression of wild-type lamin A, which interacts with the speckle scaffold protein SON, partially restores the organizational and transcriptional defects, while the disease-associated E161K mutant disrupts SON binding and shows limited recovery. Our results elucidate the multifaceted roles of lamins in nuclear organization and link their dysfunction to the pathogenesis of laminopathies.

Humans↗
PubMed2026

Subnuclear genome compartmentalization controls bivalent chromatin activity.

The nuclear genome is spatially organized into a three-dimensional architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.

Humans↗
PubMed2025

High temperature-responsive DEAR4 condensation confers thermotolerance through recruiting TOPLESS in Arabidopsis nucleus.

Global warming is harmful to plants and threatens crop yields in the world. In contrast to other abiotic stresses, the molecular mechanisms for plant high temperature perception and signaling are still not fully understood. Here, we report that transcription factor DREB AND EAR MOTIF PROTEIN 4 (DEAR4) positively regulates heat tolerance in Arabidopsis thaliana. We further reveal that DEAR4 proteins undergo liquid-liquid phase separation (LLPS) and high temperature could induce DEAR4 condensate formation in the nucleus. Moreover, DEAR4 recruits the transcriptional co-repressor TOPLESS (TPL) into the nuclear speckles under high temperature. The high temperature triggered DEAR4-TPL co-condensates enhance their transcriptional repression activity through modulating histone deacetylation levels of GASA5, which is a reported negative regulator of HEAT SHOCK PROTEINs (HSPs). A genome-wide transcriptional landscape study confirms that DEAR4 induces the expression of multiple HSPs. Taken together, we illustrate a transcriptional repression mechanism mediated by DEAR4 through LLPS to confer plants thermotolerance and open a new avenue for translating this knowledge into crops for improving their heat resistance.

Arabidopsis↗
PubMed2026

Epigenetic regulation of transgenes.

Gene therapy holds significant potential for treating genetic disorders, but the use of viral vectors is limited by factors such as immunogenicity, payload capacity, and high manufacturing costs. Nonviral gene delivery (NVGD) using plasmid DNA presents an attractive alternative; however, it typically provides a limited magnitude or duration of transgene expression. One potential reason for these shortcomings is the host cell's epigenetic regulation mechanisms, which can silence both viral and nonviral transgenes. Specifically, when foreign DNA enters the nucleus, it is detected by nuclear DNA sensors, such as IFI16, which initiate the assembly of a "restrictosome" or nuclear domain 10 (ND10) body. This multiprotein complex contains several components, such as PML, Speckled Proteins (e.g., SP100), DAXX, and ATRX that act as a scaffold for recruiting various epigenetic modifiers that subsequently deposit repressive histone modifications like H3K9me3 and H3K27me3 on the transgene chromatin. These marks induce DNA methylation and the subsequent condensation of plasmids or episomes into heterochromatin, which represses transgene expression. Alternatively, unmethylated CpG motifs in bacterial plasmid DNA can trigger innate immune responses in the cytosol, but this review will specifically focus on the detailed mechanisms of epigenetic regulation responsible for silencing plasmid DNA within the host cell nucleus. Addressing these nuclear defense mechanisms, potentially through strategies that manipulate DNA methylation or inhibit restrictosome activity, is crucial for advancing the development of safe, effective, and long-lasting plasmid viral and non-viral gene therapies.

Epigenesis, Genetic↗
PubMed2025

Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas.

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.

Humans↗
PubMed2024

SPOP expression is associated with tumor-infiltrating lymphocytes in pancreatic cancer.

BACKGROUND: Speckle Type POZ Protein (SPOP), despite its tumor type-dependent role in tumorigenesis, primarily as a tumor suppressor gene is associated with a variety of different cancers. However, its function in pancreatic cancer remains uncertain. METHODS: SPOP expression and the association between its expression and patient prognosis and immune function were evaluated using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), The Tumor Immune Estimation Resource 2.0 (TIMER2.0) database, cBioportal, and various bioinformatic databases. Enrichment analysis of SPOP and the association between SPOP expression with clinical stage and grade were analyzed using the R software package. Then immunohistochemistry (IHC) was used to estimate the correlation between SPOP and tumor-infiltrating lymphocytes (TILs) in patients with pancreatic cancer. RESULTS: As part of our study, we assessed that SPOP was anomalously expressed in kinds of cancers, associated with clinical stage and outcomes. Meanwhile, SPOP also played a crucial role in the tumor microenvironment (TME). The expression level of SPOP was significantly correlated to tumor-infiltrating immune cells (TICs) in pancreatic cancer. CONCLUSIONS: Our study uncovered the potential corrections in SPOP with TICs, suggesting that SPOP may act as a biomarker for immunotherapy in pancreatic cancer.

Humans↗