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Biomedical subjects

Markku Varjosalo

Publications and source records attributed to Markku Varjosalo.

4 recordsLinked to original sources
PubMed2026

BHLHE40 and ChREBP associate with hepatic enhancer clusters containing PPARα, RXRα, and HNF4 nuclear receptors.

BHLHE40/DEC1 is a basic helix-loop-helix transcription factor (TF) that regulates circadian rhythm and T-cell responses. In hepatocytes, its function and interplay with other TFs are poorly understood. Employing a genome-wide approach, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein, a sugar-sensing TF and known inducer of BHLHE40 expression. Transcriptomic analysis of primary mouse hepatocytes revealed reduced expression of genes involved in genomic stability on Bhlhe40 knockdown by siRNA. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell-cycle regulation. Strikingly, genomic binding of BHLHE40 extensively overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXRα and PPARα cofactors. Collectively, our data suggest that through cooperation with carbohydrate response-element binding protein and nuclear receptors, BHLHE40 is a central regulator of hepatic gene expression with potential to integrate inputs from nutrient signals contributing to the metabolic flexibility of the liver.

Animals↗
PubMed2025

Proximity interactome of alphavirus replicase component nsP3 includes proviral host factors eIF4G and AHNAK.

All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.

Viral Nonstructural Proteins↗
PubMed2025

Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin.

Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor β (TGF-β)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.

Animals↗