Biology subjects

Banuelos, C.

Publications and source records attributed to Banuelos, C..

3 recordsLinked to original sources

bioRxiv2023

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The first group shows decreased proliferation, genome instability, and increased sensitivity to genotoxic agents, such as PARP1/2 inhibitors. In contrast, the H3K36M HNSCC models with steady H3K27me3 levels do not exhibit these characteristics unless H3K27me3 levels are elevated, either by DNA hypomethylating agents or by inhibiting the H3K27me3 demethylases KDM6A/B. Mechanistically, we found that H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, we found that aberrant H3K27me3 levels induced by H3K36M expression is not a bona fide epigenetic mark in HNSCC since it requires continuous expression of H3K36M to be inherited. Moreover, increased sensitivity of H3K36M HNSCC models to PARP1/2 inhibitors solely depends on the increased H3K27me3 levels. Indeed, aberrantly high H3K27me3 levels decrease BRCA1 and FANCD2-dependent DNA repair, resulting in higher sensitivity to DNA breaks and replication stress. Finally, in support of our in vitro findings, a PARP1/2 inhibitor alone reduce tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a H3K36M HNSCC xenograft model with consistent H3K27me3 levels, a combination of PARP1/2 inhibitors and agents that upregulate H3K27me3 proves to be successful. In conclusion, our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.

cancer biology↗

bioRxiv2022

D2 dopamine receptor expression, sensitivity to rewards, and reinforcement learning in a complex value-based decision-making task

In the basal ganglia, different dopamine subtypes have opposing dynamics at post-synaptic receptors, with the ratio of D1 to D2 receptors determining the relative sensitivity to gains and losses, respectively, during value-based learning. This effective sensitivity to reward feedback interacts with phasic dopamine levels to determine the effectiveness of learning, particularly in dynamic feedback situations where frequency and magnitude of rewards need to be integrated over time to make optimal decisions. Using both simulations and behavioral data in humans, we evaluated how reduced sensitivity to losses, relative to gains, leads to suboptimal learning in the Iowa Gambling Task (IGT), a complex value-learning task. In the behavioral data, we tested individuals with a variant of the human dopamine receptor D2 (DRD2; -141C Ins/Del and Del/Del) gene that associates with lower levels of D2 receptor expression (N=119) and compared their performance to non-carrier controls (N=319). The magnitude of the reward response was measured by looking at ventral striatal (VS) reactivity to rewards in the Cards task using fMRI. DRD2 variant carriers had generally lower performance in the IGT than non-carriers, consistent with reduced sensitivity to losses. There was also a positive association between VS reactivity and performance in the IGT, however, we found no statistically significant difference in this effect between DRD2 carriers and non-carriers. Thus, while reduced D2 receptor expression was associated with less efficient learning in the IGT, we did not find evidence for the moderation of this effect by the magnitude of the reward response.

neuroscience↗

bioRxiv2019

How structural brain network topologies associate with cognitive abilities in a value-based decision-making task

Value-based decision-making relies on effective communication across disparate brain networks. Given the scale of the networks involved in adaptive decision-making, variability in how they communicate should impact behavior; however, precisely how the topological pattern of structural connectivity of individual brain networks influences individual differences in value-based decision-making remains unclear. Using diffusion MRI, we measured structural connectivity networks in a sample of community dwelling adults (N=124). We used standard graph theoretic measures to characterize the topology of the networks in each individual and correlated individual differences in these topology measures with differences in the Iowa Gambling Task. A principal components regression approach revealed that individual differences in brain network topology associate with differences in optimal decision-making, as well as associate with differences in each participants sensitivity to high frequency rewards. These findings show that aspects of structural brain network organization can constrain how information is used in value-based decision-making.\n\nAbbreviationsMRI - Magnetic Resonance Imaging; IGT - Iowa Gambling Task; DWI - Diffusion Weighted Imaging; QSDR - Q-Space Diffeomorphic Reconstruction; PCA - Principal Components Analysis; GLM - Generalized Linear Models

neuroscience↗