The Good, The Bad, and The Epi(genetics) 

In the midst of the frigid high desert, enveloped by snow-capped plateaus and the echoes of manifest destiny, researchers from around the world converged to delve into the latest advancements in epigenetics and its potential in cancer therapies. Santa Fe, New Mexico served as the backdrop for this year’s Keystone Symposia: Epigenetic Mechanisms and Cancer Treatment. Here, pioneers in oncology research embarked on a journey beyond linear sequence and expression profiles, venturing into the untamed realm of epigenetics, reminiscent of the intrepid settlers of old forging westward towards new frontiers. 

At the core of discussions lay the intricate mechanisms driving diseases and the precise ways in which therapies counteracted them. Reflecting similar themes from recent chromatin conferences, nuclear condensates, chromatin accessibility, and polycomb complexes emerged as pivotal players, albeit portrayed this time as renegades responsible for aberrant gene expression. The prevailing theme of the conference was that cancer is essentially a transcription factor problem, where imbalances in factor expression lead to oncogenesis. 

This perspective propelled 3D genomics into the limelight with a number of presentations showcasing instances where the gene expression profiles (RNA-seq data) of oncogenes failed to align with transcription factor binding patterns (ChIP-seq, CUT&Run, ATAC-seq data) at gene promoters. Yet, through 3D chromatin interactions (Hi-C, Micro-C, HiChIP), researchers pinpointed distal elements intricately engaged with the oncogenes. These findings, underscored by perfect alignment between transcription factor binding at the distal element and the observed expression profile, offered a distinct signature to monitor as both a biomarker and a target for future therapeutic developments. 

Some researchers ventured further by crafting novel therapies around these epigenetic mechanisms. As emphasized by a keynote speaker, “you must really know the biology and you must really know the chemistry” as an imperative to decipher the structure and function of these transcription factors, enabling the precise targeting with specific molecules to disrupt their function. Collaboration emerged as a linchpin in these endeavors, with pharmaceutical research programs relying on academic researchers for biological insights, their chemists for therapeutic production, and translational researchers for the testing ground. Ultimately, the focus circled back to mechanism – be it in the context of treatment or disease pathology. 

Amidst the cutting-edge research and next-generation sequence-based assays, the enduring relevance of the western blot was evident. Though perhaps a tad metaphorically fitting given the meeting’s locale, the western blot served as tangible evidence of mechanism discovery or suppression in therapy. As researchers readied their wagons and secured their saddles to depart, a profound sense lingered – much like the old west, epigenetics beckons with boundless opportunities for those daring to explore and conquer the uncharted territories of this new 3D landscape. 

3D Genomics, Epigenetics, Hi-C, HiChIP, Micro-C, Omni-C
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