Blue Therapeutics (United States)

Abstract Transcription factors (TFs) are key effectors of enhancer activity. MYB is a critical hematopoietic TF that is frequently dysregulated in cancer. Despite its well-established role, the exact mechanisms by which MYB influences enhancer function—and the specific stages of enhancer activation at which it operates—remain poorly understood. Using high resolution Micro-Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at specific MYB binding sites are lost. Loss of these interactions, together with other hallmarks of enhancer activity—reduced H3 lysine-27 acetylation and enhancer RNA transcription—correlates with significant downregulation of target gene expression in leukemia, indicating that MYB mediates transcription activation via maintenance of enhancer function. When anchored to DNA within a gene desert region that is devoid of histone marks and active transcription, the MYB transactivation domain is sufficient and necessary for the nucleation of an enhancer-like region. This results in the activation of transcription from distal cryptic elements and the establishment of long-range chromatin interactions up to 400 kb away from the anchor point. Together, these results indicate that MYB activity alone is sufficient to induce long-range interactions and transcription, achieving this through highly precise enhancer-promoter crosstalk.

The opioid crisis is a serious public health issue of epidemic proportions, building over the past decades. Prescription opioid abuse is one of the key sources of this issue. While pain is usually managed using pharmacological approaches, such as opioids, they produce several unwanted side effects – including respiratory depression and addiction – non-pharmacological approaches can be significant with minimal or no side effects. Recent developments in technology, such as Virtual Reality (VR), show considerable promise for main-stream adoption as one of the non-pharmacological interventions. Preventing a patient’s transition from acute to chronic pain is one instance where VR can presumably be effective. However, challenges remain due to the inherent subjectivity and lack of clear baselines in clinical intervention studies. Here, we review recent studies on the application of VR as a treatment for acute and chronic pain management to primarily understand key technical challenges faced by VR. The secondary goal of this work is to identify possible options to tackle some of the key challenges. Design considerations emerge as one critical component in improving patient engagement.