# Control of protein degradation and transcriptional dynamics in the auxin response

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $373,799

## Abstract

Coordinating the timing of responses both within and between cells is critical for multicellular behaviors like
development. One way to evolve (or engineer) a molecular pacer is via induced turnover of transcriptional
repressors acting at multiple loci—a solution observed in diverse eukaryotes. Yet we know remarkably little
about how protein degradation kinetics translate into downstream transcriptional responses that lead to
outcomes like changes in cell fate. One possible reason is the lack of available models for high-resolution
structure-function analysis of degradation-linked transcriptional activation. We have leveraged the auxin
response, at the heart of nearly every aspect of plant biology, as a model to investigate general principles
underlying ubiquitin-mediated degradation and its connection to transcriptional activation and morphogenesis.
The small-molecule triggered degradation in the auxin pathway offers a unique advantage for these studies,
and has facilitated our engineering of auxin-induced degradation and transcriptional activation in yeast. Our
extensive work with our ‘AuxInYeast’ system has led to a central hypothesis: the auxin system functions as a
developmental timer in plants, and similar logic circuits act in many eukaryotes. One recent insight into the
molecular mechanism underlying the auxin timer was our discovery that transcriptional repression in the auxin
circuit, conferred by a Groucho/Tup1/TLE-type corepressor called TPL, requires interaction with the Mediator
complex. Our results suggest a new model of transcriptional regulation where corepressors can stabilize the
Pre-Initiation Complex in the absence of RNA Polymerase II, priming loci for rapid activation. In addition, we
have shown in transgenic plants that the rate of degradation-triggered removal of the TPL corepressor sets the
pace of de novo organogenesis in the root. Here, we will rigorously test the emergent model that corepressor-
based priming facilitates coordination of rapid transcriptional bursts at multiple loci across the genome, and
facilitates cell-cell synchrony during morphogenesis. Specific research projects will: (1) Deliver a high
spatiotemporal resolution, integrated, functional map of a single synthetic yeast locus transitioning from
repressed to active state, including composition/placement of protein complexes and chromatin modifications;
(2) Dissect the mechanism of a novel autonomous TPL repression domain we have identified that is found in
thousands of proteins, and quantify the impacts on repressive function of cancer-associated variants in select
proteins; (3) Build an in vivo cell fate tracker to probe the connection between synchrony in transcription and
morphogenesis. Together, the proposed work will provide a mechanistic framework for degradation-initiated
transcriptional activation in the auxin response, and potentially provide insights into fundamental properties in
common with many corepressor-primed systems. These insights ...

## Key facts

- **NIH application ID:** 10861715
- **Project number:** 5R35GM148135-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JENNIFER L NEMHAUSER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,799
- **Award type:** 5
- **Project period:** 2023-06-10 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861715

## Citation

> US National Institutes of Health, RePORTER application 10861715, Control of protein degradation and transcriptional dynamics in the auxin response (5R35GM148135-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861715. Licensed CC0.

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