Biology subjects

Churikov, D.

Publications and source records attributed to Churikov, D..

4 recordsLinked to original sources

bioRxiv2026

TERT drives liver tumorigenesis beyond telomere elongation

We generated two mouse models, p21/Tert and p21/TertCi, expressing either telomerase reverse transcriptase (TERT) or a catalytically inactive variant under the control of the p21 promoter. By 18-20 months of age, approximately 25% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing identified activating Ctnnb1 mutations and recurrent PP1 subunit alterations in p21/Tert tumors, whereas p21/TertCi tumors harbored activating HrasGln61Lys mutations associated with elevated C>A transversions. Both models exhibited chromosomal aberrations commonly observed in human HCC. Transcriptomic analyses revealed that {beta}-catenin-activated tumors recapitulated gene expression signatures of human HCC, while MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. Metabolically, both genotypes demonstrated increased glycolysis and suppression of gluconeogenesis, including downregulation of FBP1, but expressed distinct NRF2 target genes. Spatial profiling further revealed reduced HNF4-positive hepatocytes across tumors, independent of Hnf4 transcription, and markedly diminished immune cell infiltration particularly in {beta}-catenin-activated tumors. Collectively, these findings uncover telomere-independent functions of TERT and identify molecular and metabolic features with potential relevance for predicting immunotherapy response.

cancer biology↗

bioRxiv2025

TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert (p21+/Tert) from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders. Conditional expression of mTERT reduces metabolic disorders associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We show that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby reducing metabolic disorders. We further report that mTERT remodels the landscape of macrophages in AT of obese mice. Strikingly, inactivation of mTERT catalytic activity in p21+/Tert (p21+/TertCi) mice suppresses the promotion of adipocyte formation, but neither affects attenuation of senescence nor macrophage remodeling. These results highlight mTERTs canonical and non-canonical functions in reducing obesity-associated metabolic disorders. Conditional expression of TERT thus appears as a potential therapeutic option for obesity.

physiology↗

bioRxiv2022

Induction of telomerase in p21-positive cells counteracts capillaries rarefaction in aging mice lung

Telomerase is required for long-term cell proliferation and linked to stem cells. This is evident in the lung where short telomeres are associated with lung dysfunction. We constructed a mouse model in which the telomerase (Tert) is expressed from the p21Cdkn1a promoter. We found that this peculiar Tert expression curb age-related emphysema and pulmonary perivascular fibrosis in old mice. In old mice lungs, such Tert expression preferentially occurs in endothelial cells where it reduces the number of senescent endothelial cells. Remarkably, we report that Tert counteracts the age-related decline in capillary density. This was associated with an increased number of Cd34+ cells identified as a subclass of capillary cells with proliferative capacity. Expression of catalytically inactive Tert neither prevents the decline of capillary density in old mice nor protects against age-related emphysema and fibrosis. These findings reveal that telomerase decreases age-decline of pulmonary functions by sustaining microvasculature regeneration and outgrowth.

molecular biology↗

bioRxiv2019

UFMylation of MRE11 is essential for telomere length and hematopoietic stem cell survival

Genetic studies using knockout mouse models provide strong evidence for the essential role of the ubiquitin-like protein UFM1 for hematopoiesis, especially erythroid development, yet its biological roles in this process are largely unknown. Here we have identified a UFL1-dependent UFMylation of the MRE11 nuclease on the K281 and K282 residues. We show that Hela cells lacking the specific UFM1 E3 ligase display severe telomere shortening. We further demonstrate either by deleting UFM1 or by mutating MRE11 UFMylation sites that preventing MRE11 UFMylation impacts its interaction with the telomere protein TRF2. However, the MRE11 function in double-strand-break repair remains intact. We validate these results in vivo by showing that Zebrafish knockouts for the genes ufl1 and ufm1 have shorter telomeres in hematopoietic cells. Here we present UFMylation has a new mechanisms of regulation for telomere length maintenance with a role in hematopoiesis. Key pointsModification of MRE11 by UFM1 regulates telomere maintenance and cell death in HSCs Scientific categoryUFMylation, telomere maintenance, hematopoietic stem cell survival.

molecular biology↗