# Mediator kinases as interferon antagonists in Down Syndrome

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $494,478

## Abstract

SUMMARY
This collaborative project seeks to gain a deep mechanistic understanding of the Mediator kinases (CDK8 and
CDK19) and their roles in driving hyper-active interferon (IFN) signaling in Down syndrome (DS). A chronic
inflammatory state underlies the DS condition and contributes to its co-morbidities; consequently, a means to
dampen IFN activation could have broad therapeutic benefits. CDK8 and CDK19 each represent druggable
targets and, as potent activators of IFN responses, inhibition of their function could effectively antagonize
runaway IFN signaling in DS. CDK8 and its paralog, CDK19, are considered “Mediator kinases” because of their
stable, but reversible, association with the 26-subunit Mediator complex. Mediator is a global regulator of RNA
polymerase II (pol II) activity, which transcribes all protein-coding and many non-coding RNAs in the human
genome. CDK8 and CDK19 have each been shown to help drive transcriptional responses to IFN cytokines,
which are universal regulators of inflammation and immune function. Here, we seek to define their essential—
yet poorly understood—cellular and mechanistic roles in the context of DS (Biobank-matched D21 and T21 cells)
and IFN signaling. We will combine sophisticated cell-based methods (e.g. transcriptomics and metabolomics)
with detailed, cutting-edge biochemical approaches to allow rigorous and reliable assessment of the mechanisms
by which CDK8 vs. CDK19 control IFN responses in DS individuals. In Aim 1, we will probe the role of Mediator
kinase activity, whereas in Aim 2 we will focus on the CDK19 protein, which serves key structural/scaffolding
roles to enable robust transcriptional responses upon IFN stimulation. Transcriptomic (RNA-seq and PRO-seq)
and metabolomics approaches will be applied in Aims 1 and 2, to assess T21-specific signatures (including
potential splicing defects) and to identify how CDK8 and/or CDK19 impact cellular responses to IFN. These
experiments will also uncover how sequence-specific, DNA-binding transcription factors (TFs) are differentially
mobilized in T21 vs. D21 cells, including during IFN stimulation. As part of this, we will establish how CDK8 and
CDK19 independently control TF activation or repression, through kinase-dependent or -independent
mechanisms. In Aim 3, we will perform detailed in vitro studies to define the molecular mechanisms by which
Mediator kinases regulate pol II transcription initiation, promoter-proximal pausing, or elongation. Mechanistic
findings will then be probed further in cells, to better characterize their significance in DS and related IFN
signaling cascades. Collectively, these experiments (Aims 1-3) may help establish Mediator kinases (CDK8 &
CDK19) as viable therapeutic targets to antagonize hyper-active IFN signaling in DS. Moreover, the balance of
targeted/mechanistic studies with discovery-based approaches may yield new and unanticipated therapeutic
strategies with relevance for DS and its associated co-morbidities, w...

## Key facts

- **NIH application ID:** 10114912
- **Project number:** 1R01AI156739-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Dylan J Taatjes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,478
- **Award type:** 1
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114912

## Citation

> US National Institutes of Health, RePORTER application 10114912, Mediator kinases as interferon antagonists in Down Syndrome (1R01AI156739-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10114912. Licensed CC0.

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