# Developmental Regulation of Gene Expression by Long Undecoded Transcript Isoforms

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $330,729

## Abstract

PROJECT SUMMARY
Dynamic gene expression programs drive essential biological processes including cellular differentiation and
stress response pathways. During these processes, cells must simultaneously activate and repress distinct
clusters of genes to facilitate the necessary shift in proteome synthesis. How gene repression is achieved
amidst widespread transcriptional activation is not well understood. My lab has recently discovered a
regulatory mechanism in budding yeast meiosis that achieves such coordination. Central to this mechanism is
the transcription factor-driven expression of an alternative mRNA isoform called LUTI (Long Undecoded
Transcript Isoform) from a distal gene promoter. This mRNA cannot produce functional protein due to
competitive upstream open reading frames (uORFs) in its extended 5' leader. Instead, its transcription serves
to repress the canonical mRNA transcription in cis through chromatin modifications, ultimately leading to
inhibition of protein synthesis. Therefore, transcription of these mRNAs, despite carrying a full coding region,
can directly cause gene repression. Consequently, a single transcription factor can synchronously activate and
repress protein synthesis for distinct sets of genes, depending whether it binds to a canonical or a LUTI
promoter, respectively. Furthermore, this mechanism is tunable and reversible, making it ideal for fluid cell
state transitions that rely on dynamic changes in gene expression.
 The LUTI-based mechanism is neither limited to meiosis nor restricted to budding yeast, as it occurs
during the unfolded protein response and is conserved in human cells. Importantly, the two essential branches
of this regulation are both associated with human disease. First, misregulation of alternative transcription start
sites is widespread across multiple cancers. Second, disruption of uORF expression is linked to a variety of
disorders ranging from gonadal dysgenesis to melanoma. Therefore, dissecting the mechanism and biological
scope of LUTI-based regulation is critical for our understanding of how cells control their gene expression
programs, and how mistakes in this process can lead to pathological states. This proposal seeks to address
fundamental questions regarding the mechanism and function of LUTI-based regulation in yeast and human
cells. Experiments proposed in aim 1 will investigate how transcriptional repression is achieved by activation of
LUTI promoters during meiosis and the unfolded protein response, where LUTIs are pervasively expressed.
Experiments proposed in aim 2 will elucidate how the LUTI-based regulation is integrated into larger signaling
networks to ensure precise and robust cell state transitions. Finally, experiments proposed in aim 3 will
determine the evolutionarily conserved aspects of LUTI-based regulation and uncover the biological roles of
LUTIs during human embryonic stem cell differentiation. The combination of studies described in this proposal
will illuminat...

## Key facts

- **NIH application ID:** 10097910
- **Project number:** 1R01GM140005-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Elcin Unal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,729
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10097910

## Citation

> US National Institutes of Health, RePORTER application 10097910, Developmental Regulation of Gene Expression by Long Undecoded Transcript Isoforms (1R01GM140005-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10097910. Licensed CC0.

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