Abstract 5957: Transcriptional alterations in neoplastic transformation

Cancer Research · 2026-04-03

Abstract Genetic alterations aberrantly turn on oncogenic transcription programs, thereby driving cellular transformation and tumor progression. Transcription comprises multiple steps, including initiation, promoter-proximal pausing, pause release, elongation, and termination. Because these steps are essential in both normal and cancer cells, targeting transcription has historically lacked therapeutic specificity. To address this problem, a key unmet need for the field is to identify differential features of transcription between normal and transformed cells to then exploit factors that regulate those distinctions. In line with this goal, we have identified two distinct changes in global transcription dynamics in normal breast cells undergoing oncogenic transformation. First, oncogenic transformation is associated with global increases in transcription elongation rate, or the speed by which RNA Polymerase II (Pol II) travels in gene bodies. This heightened rate is not just observed at genes inducible upon transformation, suggesting that oncogenic signaling may exploit elongation control to globally alter the transcriptome to advance cellular transformation. Second, oncogenic transformation is associated with decreases in promoter proximal pausing, implying that one of two potential mechanisms is elicited once cells undergo this cell state change: (i) increased premature termination to evict Pol II off promoters, and/or (ii) decreased Pol II recruitment. Given these findings, I hypothesize that oncogenic transformation requires global alterations to multiple transcription steps, and that perturbation of factors that selectively regulate these steps may obstruct the transformation process without killing normal cells, enabling the identification of targetable therapeutic approaches. Citation Format: Usman Hyder, Nova Fong, Benjamin Erickson, David Bentley. Transcriptional alterations in neoplastic transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5957.

Author response: Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

2025-02-10

The Mediator-associated kinases CDK8 and CDK19 help drive inflammatory responses to interferon, and it is discovered that kinase-dependent transcriptional responses manifest in part through splicing changes and lipid metabolites.

Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

eLife · 2025-01-17

Abstract Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75min - 24h timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad up-regulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

Demonstrating Shape-Kit: A Design Toolkit for Crafting On-Body Expressive Haptics

2025-04-23 · 1 citations

Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

eLife · 2025-02-10 · 1 citations

Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

Author response: Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

2025-01-17

Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75min - 24h timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad up-regulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

PP1/PNUTS Phosphatase Binds the Restrictor Complex and Stimulates RNA pol II Transcription Termination

SSRN Electronic Journal · 2025-01-01

PP1/PNUTS phosphatase binds the restrictor complex and stimulates RNA Pol II transcription termination

Cell Reports · 2025-04-16 · 4 citations

Publisher of over 50 scientific journals across the life, physical, earth, and health sciences, both independently and in partnership with scientific societies including Cell, Neuron, Immunity, Current Biology, AJHG, and the Trends Journals.

Shape-Kit: A Design Toolkit for Crafting On-Body Expressive Haptics

2025-04-24 · 3 citations

Driven by the vision of everyday haptics, the HCI community is advocating for "design touch first" and investigating "how to touch well." However, a gap remains between the exploratory nature of haptic design and technical reproducibility. We present Shape-Kit, a hybrid design toolkit embodying our "crafting haptics" metaphor, where hand touch is transduced into dynamic pin-based sensations that can be freely explored across the body. An ad-hoc tracking module captures and digitizes these patterns. Our study with 14 designers and artists demonstrates how Shape-Kit facilitates sensorial exploration for expressive haptic design. We analyze how designers collaboratively ideate, prototype, iterate, and compose touch experiences and show the subtlety and richness of touch that can be achieved through diverse crafting methods with Shape-Kit. Reflecting on the findings, our work contributes key insights into haptic toolkit design and touch design practices centered on the "crafting haptics" metaphor. We discuss in-depth how Shape-Kit's simplicity, though remaining constrained, enables focused crafting for deeper exploration, while its collaborative nature fosters shared sense-making of touch experiences.

Maf1 Cooperates with Progesterone Receptor to Repress RNA Polymerase III Transcription of Select tRNAs

bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-16 · 1 citations

Progesterone receptors (PR) can regulate transcription by RNA Polymerase III (Pol III), which transcribes small non-coding RNAs, including all transfer RNAs (tRNAs). We have previously demonstrated that PR is associated with the Pol III complex at tRNA genes and that progestins downregulate tRNA transcripts in breast tumor models. To further elucidate the mechanism of PR-mediated regulation of Pol III, we studied the interplay between PR, the Pol III repressor Maf1, and TFIIIB, a core transcription component. ChIP-seq was performed for PR, the Pol III subunit POLR3A, the TFIIIB component Brf1, and Maf1 in breast cancer cells with or without progestin treatment. Upon progestin exposure, PR localized to approximately half of POLR3A-occupied tRNA genes, with Maf1 co-recruited to many of these PR-POLR3A sites. While progestin treatment did not significantly alter the number of tRNA genes occupied by Pol III or Brf1, Brf1 occupancy was stabilized, as indicated by increased peak amplitudes. Analysis of nascent tRNA transcription revealed a specific progestin-induced downregulation of approximately one-third of highly expressed tRNA genes. This repression was significantly reduced by Maf1 knockdown, indicating that Maf1 is necessary for PR-mediated tRNA transcription downregulation. Overall, these findings demonstrate a ligand-dependent PR-mediated repression of tRNA transcription through Maf1.