Fox, J. A. | Search bioRxiv

bioRxiv2024

BET Degraders Reveal BRD4 Disruption of 7SK and P-TEFb is Critical for Effective Reactivation of Latent HIV in CD4+ T-cells

HIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents to modulate host pathways which directly or indirectly facilitate viral reactivation. Inhibition of BET (bromo and extra-terminal domain) family member BRD4 reverses HIV latency, but enthusiasm for the use of BET inhibitors in HIV cure studies is tempered by concerns over inhibition of other BET family members and dose-limiting toxicities in oncology trials. Here we evaluated the potential for bivalent chemical degraders targeted to the BET family as alternative latency reversal agents. We observed that despite highly potent and selective BRD4 degradation in primary CD4+ T-cells from ART-suppressed donors, BRD4 degraders failed to induce latency reversal as compared to BET inhibitors. Further, BRD4 degraders failed to mimic previously observed synergistic HIV reactivation between BET inhibitors and an activator of the non-canonical NF-{kappa}B pathway. Mechanistic investigation of this discrepancy revealed that latency reversal by BET inhibitors is not related to the abatement of competition between Tat and BRD4 for P-TEFb, but rather the ability of BRD4 to disrupt 7SK and increase the levels of free P-TEFb. This activity is dependent on the shift of BRD4 from chromatin-bound to soluble and retargeting of P-TEFb to chromatin which is dependent on intact BRD4 but independent of the bromodomains.

molecular biology↗

bioRxiv2023

Counter-gradient variation in gene expression between fish populations facilitates colonization of low-dissolved oxygen environments

The role of phenotypic plasticity during colonization remains unclear due to the shifting importance of plasticity across timescales. Over time, genetic responses can reduce plasticity such that species in a novel environment show higher levels of plasticity than those with a longer evolutionary timescale in the environment. Therefore, comparing species in the early stages of colonization to long-established species provides a powerful approach for uncovering the role of phenotypic plasticity during different stages of colonization. We compared gene expression between the cyprinid fish Enteromius apleurogramma, a species that has undergone a recent range expansion, and E. neumayeri, a long-established native species in the same region, caught from low-dissolved oxygen (DO) and high-DO habitats. We sampled tissue either immediately after capture from the field or after a two-week acclimation under high-DO conditions, allowing us to test for both evolved and plastic differences in low-DO vs high-DO populations of each species. We found that most genes showing evolved differences in gene expression did not overlap with those showing plastic differences in gene expression. However, in the genes that did overlap, there was counter-gradient variation such that plastic and evolved gene expression responses were in opposite directions in both species. Additionally, E. apleurogramma had higher levels of plasticity and evolved divergence in gene expression between field populations. We suggest that the higher level of plasticity and counter-gradient variation may have allowed rapid genetic adaptation in E. apleurogramma and facilitated colonization. This study shows how counter-gradient variation may impact colonization of divergent oxygen environments.

evolutionary biology↗