Kulchycki, J. | Search bioRxiv

bioRxiv2026

Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTADA) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFCPL) and the VTA. Chemogenetic inhibition of mPFCPL[->]VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

neuroscience↗

bioRxiv2026

A Sensitized ENU Mutagenesis Screen for Thrombosis Modifiers Identifies Suppressor Variants in Non-mutagenized Parental Generations Due to Antithrombotic Selective Pressures

Thrombosis is a leading cause of morbidity and mortality. We used a mouse forward genetic ENU screen to identify genomic variants that suppress F5L/L Tfpi+/- lethal thrombosis. Surviving F5L/L Tfpi+/- mice from our Modifier of Factor 5 Leiden 16 (MF5L16) ENU line were subjected to whole-genome sequencing analysis. This revealed that instead of an ENU-induced mutation, four mutations introduced from our F5L/L breeding stock were responsible for survival, which we named sMF5L1-4 for spontaneous Modifier of Factor 5 Leiden. In our colony, F5L/L female breeders carrying all four sMF5L mutations produced more litters and offspring than breeders with three or fewer mutations (p<0.006). Genotyping of 13 additional MF5L lines demonstrated that the four sMF5L mutations were present in all lines and were consistently associated with survival. Of these four mutations, a single G to A intergenic variant on Chromosome 18 (Chr18A, sMF5L4), was most significantly associated with survival (p=0.003), with [~]15% penetrance for conferring the survival phenotype. Furthermore, platelet aggregation was significantly reduced in Chr18A mice, suggesting an additional mechanism by which Chr18A could suppress lethal thrombosis. Comparative transcriptomics analysis of livers from Chr18A mice versus wildtype littermate controls revealed a small number of differentially expressed genes both known and unknown to affect thrombosis. In summary, we have identified four variants exerting a significant selective breeding advantage along with antithrombotic effects. Superimposing our mutagenesis screen on a selective background illustrates the interplay of natural strain background variants and de novo ENU mutations in suppressing F5L/L Tfpi+/- lethal thrombosis.

genetics↗