About

Professor Dylan J. Taatjes is a researcher at the University of Colorado Boulder, leading the Taatjes Lab which focuses on understanding the molecular mechanisms that control human gene expression. His work investigates how transcription and signaling pathways are altered during development and disease, with particular emphasis on sequence-specific, DNA-binding transcription factors and the Pre-Initiation Complex (PIC). The PIC, which includes components such as Mediator, RNA polymerase II, and various general transcription factors, plays a crucial role in regulating the activity of RNA polymerase II, the enzyme responsible for transcribing all protein-coding genes and most non-coding RNAs in the human genome. Professor Taatjes's research aims to elucidate how complexes like Mediator, TFIID, and TFIIH regulate transcription initiation and post-initiation processes, utilizing a variety of experimental techniques including biochemical, biophysical, molecular, cell biology, metabolomics, proteomics, and transcriptomics. His work contributes to a deeper understanding of gene regulation mechanisms in human development and disease.

Research topics

• Biology
• Cell biology
• Computational biology
• Computer Science
• Genetics
• Molecular biology
• Biochemistry
• Medicine
• Internal medicine

Selected publications

• Histone Deacetylase Inhibitor Largazole Deactivates A Subset of Superenchancers and Causes Mitotic Chromosome Mis-alignment by Suppressing SP1 and BRD4

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-01 · 3 citations

  preprintOpen access

  Histone deacetylase inhibitors have been investigated as potential therapeutic agents for cancer and other diseases. HDIs are known to promote histone acetylation, resulting in an open chromatin conformation and generally increased gene expression. In previous work, we reported that a subset of genes, particularly those regulated by superenhancers, can be suppressed by the HDAC inhibitor largazole. To elucidate the molecular mechanisms underlying gene repression by largazole, we conducted transposase-accessible chromatin sequencing, ChIP-seq, and RNA-seq studies. Our findings revealed that while largazole treatment generally enhances chromatin accessibility, it selectively decreases the accessibility of a subset of superenhancer regions. These genomic regions, showing the most significant changes in the presence of largazole, were enriched with transcription factor binding motifs for SP1, BRD4, CTCF, and YY1. ChIP-seq analysis confirmed reduced binding of BRD4 and SP1 at their respective sites on chromatin, particularly at superenhancers regulating genes such as ID1, c-Myc and MCMs. Largazole exerts its effects by inhibiting DNA replication, RNA processing, and cell cycle progression, partially through the suppression of SP1 expression. Depletion of SP1 by shRNA mimics several key biological effects of largazole and increases cellular sensitivity to the drug. Specific to cell cycle regulation, we demonstrated that largazole disrupts G/M transition by interfering with chromosome alignment during metaphase, a phenotype also observed with SP1 depletion. Our results suggest that largazole exerts its growth-inhibitory effect by suppressing BRD4 and SP1 at super-enhancers, leading to cytostatic responses and mitotic dysfunction.

  PublisherOA PDFDOI

• Real-time visualization of reconstituted transcription reveals RNA polymerase II activation mechanisms at single promoters

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-06 · 5 citations

  preprintOpen accessSenior authorCorresponding

  RNA polymerase II (RNAPII) is regulated by sequence-specific transcription factors (TFs) and the pre-initiation complex (PIC): TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, Mediator. TFs and Mediator contain intrinsically-disordered regions (IDRs) and form phase-separated condensates, but how IDRs control RNAPII function remains poorly understood. Using purified PIC factors, we developed a Real-time In-vitro Fluorescence Transcription assay (RIFT) for second-by-second visualization of RNAPII transcription at hundreds of promoters simultaneously. We show rapid RNAPII activation is IDR-dependent, without condensate formation. For example, the MED1-IDR can functionally replace a native TF, activating RNAPII with similar (not identical) kinetics; however, MED1-IDR squelches transcription as a condensate, but activates as a single-protein. TFs and Mediator cooperatively activate RNAPII bursting and re-initiation and surprisingly, Mediator can drive TF-promoter recruitment, without TF-DNA binding. Collectively, RIFT addressed questions largely intractable with cell-based methods, yielding mechanistic insights about IDRs, condensates, enhancer-promoter communication, and RNAPII bursting that complement live-cell imaging data.

  PublisherDOI

• Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

  eLife · 2025-02-10 · 1 citations

  articleOpen accessSenior author

  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.

  PublisherDOI

• TF Profiler: a transcription factor inference method that broadly measures transcription factor activity and identifies mechanistically distinct networks

  Genome biology · 2025-04-09 · 2 citations

  articleOpen access

  TF Profiler is a method of inferring transcription factor (TF) regulatory activity, i.e., when a TF is present and actively participating in the regulation of transcription, directly from nascent sequencing assays such as PRO-seq and GRO-seq. While ChIP assays have measured DNA localization, they fall short of identifying when and where the effector domain of a transcription factor is active. Our method uses RNA polymerase activity to infer TF effector domain activity across hundreds of data sets and transcription factors. TF Profiler is broadly applicable, providing regulatory insights on any PRO-seq sample for any transcription factor with a known binding motif.

  PublisherOA PDFDOI

• TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network

  Science Advances · 2025-02-28 · 8 citations

  articleOpen accessSenior authorCorresponding

  How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo-electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct transcription factors (TFs) regulate constitutive versus stimulus-responsive genes. Accordingly, stimulus-responsive TFs were refractory to CDK7 inhibition whereas constitutively active "core" TFs were repressed. Core TFs (n = 78) are predominantly promoter associated and control cell cycle and proliferative gene expression programs across cell types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in core TFs and RB1. Moreover, CDK7 inhibition depleted core TF protein levels within hours, consistent with durable target gene suppression. Thus, a major but unappreciated biological function for CDK7 is regulation of a TF cohort that drives proliferation, revealing an apparent universal mechanism by which CDK7 coordinates RNAPII transcription with cell cycle CDK regulation.

  PublisherOA PDFDOI

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

  2025-01-17

  peer-reviewOpen accessSenior author

  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.

  PublisherDOI

• Multi-omics and biochemical reconstitution reveal CDK7-dependent mechanisms controlling RNA polymerase II function at gene 5’- and 3’-ends

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-09

  preprintOpen accessSenior authorCorresponding

  CDK7 regulates RNA polymerase II (RNAPII) initiation, elongation, and termination through incompletely understood mechanisms. Because contaminating kinases precluded CDK7 analysis with nuclear extracts, we completed biochemical assays with purified factors. Reconstitution of RNAPII transcription initiation showed CDK7 inhibition slowed and/or paused RNAPII promoter-proximal transcription, which reduced re-initiation. These CDK7-regulatory functions were Mediator- and TFIID-dependent. Similarly in human cells, CDK7 inhibition reduced transcription by suppressing RNAPII activity at promoters, consistent with reduced initiation and/or re-initiation. Moreover, widespread 3'-end readthrough transcription was observed in CDK7-inhibited cells; mechanistically, this occurred through rapid nuclear depletion of RNAPII elongation and termination factors, including high-confidence CDK7 targets. Collectively, these results define how CDK7 governs RNAPII function at gene 5'-ends and 3'-ends, and reveal that nuclear abundance of elongation and termination factors is kinase-dependent. Because 3'-readthrough transcription is commonly induced during stress, our results further suggest regulated suppression of CDK7 activity may enable this RNAPII transcriptional response.

  PublisherOA PDFDOI

• Regulation of RNA polymerase II transcription through re-initiation and bursting

  Molecular Cell · 2025-05-01 · 9 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

  eLife · 2025-01-17

  preprintOpen accessSenior author

  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.

  PublisherDOI

• Real-time visualization of reconstituted transcription reveals RNAPII activation mechanisms at single promoters

  Cell Reports · 2025-09-01 · 3 citations

  articleOpen accessSenior author

  RNA polymerase II (RNAPII) is regulated by sequence-specific transcription factors (TFs) and the pre-initiation complex (PIC): TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and Mediator. TFs, Mediator, and RNAPII contain intrinsically disordered regions (IDRs) and form phase-separated condensates, but how IDRs control RNAPII function remains poorly understood. Using purified PIC factors, we developed a real-time in vitro fluorescence transcription (RIFT) assay for second-by-second visualization of transcription at hundreds of promoters simultaneously. Our results establish IDRs as essential for rapid RNAPII activation, without condensate formation. For example, HSF1 condensates and single molecules function identically, whereas MED1-IDR can functionally replace HSF1 but activates RNAPII with slower kinetics. Through their IDRs, Mediator and TFs rapidly and synergistically activate RNAPII bursting and re-initiation, and surprisingly, Mediator drives TF-promoter recruitment without TF-DNA binding. Importantly, RIFT directly addresses questions largely intractable with cell-based methods, yielding mechanistic insights about condensates, IDRs, enhancer-promoter communication, and RNAPII bursting that complement live-cell imaging data.

  PublisherDOI

Recent grants

• NIH Grant R21CA175849

  NIH · $385k · 2015

• NIH Grant R03AG035228

  NIH · $122k · 2012

• Collaborative Research: Elucidating Pre-initiation Complex Assembly and Transcription Initiation by Pol-II Using Advanced Single Molecule and Microfluidic Methods

  NSF · $600k · 2013–2019

• NIH Grant R01CA127364

  NIH · $1.1M · 2012

• TFIIH and Transcription Regulation

  NIH · $2.2M · 2016–2021

Frequent coauthors

• Robin D. Dowell

  University of Colorado Anschutz Medical Campus

  51 shared

• Cecilia B. Levandowski

  University of Colorado Boulder

  46 shared

• Benjamin Erickson

  University of Colorado Boulder

  45 shared

• David L. Bentley

  45 shared

• Merve Çakır

  Duke University

  38 shared

• Andrew M. Waters

  University of Cincinnati

  38 shared

• Shannon J. McCall

  Duke University Health System

  38 shared

• Alejandro Barrera

  Duke University

  38 shared

Labs

• Taatjes LabPI

  Not provided