Biology subjects

Niskanen, H.

Publications and source records attributed to Niskanen, H..

7 recordsLinked to original sources

bioRxiv2026

Nuclear mTOR-Polycomb synergism at developmental gene promoters prone to activation

Pluripotent cells hold the capacity to differentiate into cells with diverse functions, enabling development and regeneration. The balance between local epigenetic repression and maintaining the potential for prompt transcriptional activation supports pluripotency while allowing imminent differentiation. How the activation of developmental pathways is correctly timed in sync with the environment remains poorly understood. Here we find that the cellular growth regulator mTOR selectively binds developmental gene promoters in pluripotent mouse embryonic stem cells. mTOR binding at target genes correlates with and depends on histone H2AK119 monoubiquitination (H2AK119ub1) deposited by the Polycomb Repressor Complex 1 (PRC1). Acute depletion of the whole PRC1 complex or its catalytic activity leads to depletion of mTOR at target gene promoters, whereas forced PRC1 recruitment to an artificial site brings along mTOR. At target genes, mTOR colocalizes with components of the transcription machinery and we find that mTOR-bound genes are distinctly characterized by high levels of RNA Polymerase II pausing. Our findings reveal a role of mTOR in pluripotency regulation and highlight the tight crosstalk between gene regulatory and cell growth machineries in stem cells.

molecular biology↗

bioRxiv2025

Nuclear Speckles are Regulatory Hubs for Viral and Host mRNA Expression During HSV-1 Infection

Herpes simplex virus type 1 (HSV-1) infection remodels the host nucleus, marginalizing chromatin and forming viral replication compartments (VRCs). Nuclear speckles, nuclear bodies enriched in RNA-processing factors, reposition around VRCs and undergo structural changes. While viral mRNAs are transcribed in VRCs and host transcription is largely suppressed, the nuclear routes used by viral and upregulated host transcripts and their relationship with nuclear bodies, remain unclear. We show that immediate-early (IE) viral transcripts uniquely accumulate in nuclear speckles prior to export, unlike early or late transcripts, revealing a selective nuclear speckle-dependent pathway. Similarly, host mRNAs upregulated during infection traffic into nuclear speckles after transcription. Moreover, nuclear speckles are structurally remodeled, marked by lncRNA MALAT1 removal and increased dynamics of the nuclear speckle core protein SRRM2. Lastly, we found that blocking mRNA export causes IE transcripts to accumulate in nuclear speckles, and that nuclear speckle disassembly severely impairs IE mRNA export, preventing downstream viral gene expression. These findings establish nuclear speckles as dynamic regulatory hubs that selectively facilitate the processing and export of IE viral mRNAs during HSV-1 infection. Significance statementThis study reveals how herpes simplex virus type 1 (HSV-1) manipulates structures in the nucleus termed nuclear speckles, which are essential for processing of mRNA. We discovered that early viral messages specifically pass through these nuclear speckles before exporting out of the nucleus. We find that disassembling nuclear speckles severely limits viral RNA export. Moreover, certain host cell messages also rely on nuclear speckles during infection, suggesting a shared nuclear pathway for host and viral mRNAs during infection.

cell biology↗

bioRxiv2025

MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYCs global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.

cancer biology↗

bioRxiv2025

Oligomerization enables the selective targeting of intrinsically disordered regions by small molecules

Intrinsically disordered regions (IDRs) are challenging drug targets because they lack stable interaction sites for drug-like molecules. We studied the first small molecule targeting an IDR to be evaluated in a clinical trial and found that it interacts selectively with an oligomeric form of the protein, more structured than the monomeric state, that is stabilized by interactions involving aromatic residues in regions with helical propensity. We also found that this compound alters the network of interactions defining the conformational ensemble of its target, thus affecting its condensation properties, linked to its function as a transcription factor. These findings provide a framework for developing strategies to target intrinsically disordered regions with small molecules.

biophysics↗

bioRxiv2025

Nucleus softens during herpesvirus infection

Nuclear mechanics is remodeled not only by extracellular forces but also by internal modifications, such as those induced by viral infections. During herpes simplex virus type 1 infection, the nuclear structures undergo drastic reorganization, but little is known about how nuclear mechanobiology changes as a result. We show that the nucleus softens dramatically during the infection. To understand the phenomenon, we used advanced microscopy and computational modeling. We discovered that the enlarged viral replication compartment had a low biomolecular density, partially explaining the observed nuclear softening. The mobility of the nuclear lamina decreased, which suggests increased rigidity and an inability to induce softening. However, computational modeling supported by experimental data showed that reduced outward forces, such as cytoskeletal pull and intranuclear osmotic pressure acting both on and within the nucleus, can explain the decreased nuclear stiffness. Our findings reveal that during infection, the nucleus is subject to changes in multiple mechanical forces, leading to decreased nuclear stiffness. Author SummaryDNA viruses take over the host cell nucleus, inducing dramatic structural modifications. There is currently very little knowledge of how the progression of viral infection modifies the mechanical properties of the nucleus, which are essential for various cellular processes, including gene expression and cell migration. Here, we show that the nucleus softens when herpesvirus infection progresses. We discovered that the viral replication compartment established in the central parts of the nucleus had a low biomolecular density, which may contribute to the nuclear softening. The shape and motion of the nuclear lamina suggested that it became more rigid, indicating that another mechanism was involved in the decreased elasticity. Our mechanical simulations and experiments showed that a reduction in outward forces, such as actin cytoskeleton pull or osmotic pressure, is the most likely factor in the nuclear softening. Our study provides new insights into the effects of DNA viruses on the mechanics of host cell nuclei, significantly expanding the knowledge of viral infection mechanobiology.

cell biology↗

bioRxiv2023

Progression of herpesvirus infection remodels mitochondrial organization and metabolism

Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis, and structural organization of mitochondria as herpes simplex virus type 1 lytic infection proceeds from early to late stages of infection. High-resolution microscopy and interaction analyses unveiled infection-induced emergence of rough, thin, and elongated mitochondria relocalized at the perinuclear area, a significant increase in the number and clustering of ER-mitochondria contact sites, and thickening and shortening of mitochondrial cristae. Finally, metabolic analyses demonstrated that reactivation of ATP production is accompanied by increased mitochondrial Ca2+ content and proton leakage as the infection proceeds. Overall, the significant structural and functional changes in the mitochondria triggered by the viral invasion are tightly connected to the progression of the virus infection.

microbiology↗

bioRxiv2020

Polycomb Repressive Complex 2-controlled Essrg regulates intestinal Microfold cell differentiation.

Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyers patches in the intestine responsible for monitoring and transcytosis of antigens, microorganisms and pathogens. Many transcription factors, e.g., Spi-B and Sox8, necessary to M cell differentiation have been described but the exhaustive set of factors sufficient for differentiation and development of a mature M cell remains elusive. Moreover, the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M cell development has not yet been interrogated. Here, we show that PRC2 regulates a significant set of genes during the M cell differentiation including many transcription factors. Estrogen related receptor gamma (Esrrg) is a novel M cell specific transcription factor acting on a RankL-Rank induced NF-kB pathway, upstream of Sox8 and necessary but not sufficient for a mature M cell marker Gp2 expression. To conclude, with the aid of PRC2 target survey we identified the list of developmental genes specifically implicated in M cell development and Essrg as a necessary factor for Sox8-mediated M cell differentiation.

molecular biology↗