# Roles and mechanisms of cis-regulatory IncRNAs in the p53 tumor suppressor pathway

> **NIH NIH R37** · YALE UNIVERSITY · 2021 · $359,545

## Abstract

Project Summary/Abstract
Cis-regulatory long noncoding RNAs (lncRNAs) have the unique capability to regulate the expression of
neighboring genes. Historically studied in the context of dosage compensation, there is mounting evidence that
cis-regulatory lncRNAs may also play widespread roles in normal physiology and disease development.
However, their functions and mechanisms of action have remained poorly characterized. The study proposed
herein aims to understand the role of cis-regulation in cancer biology by focusing on two lncRNAs, lncRNA-
Gadd45g and an alternative isoform of Pvt1, Pvt1alt. In preliminary studies, we have established that these
lncRNAs are directly regulated by the central tumor suppressor factor p53, that they act in cis to regulate their
neighboring genes, namely the tumor suppressor Gadd45g and the oncogene c-Myc, and that Pvt1alt is
involved in suppressing clonal growth. Based on these exciting data, we have hypothesized that cis-regulatory
lncRNAs provide an unappreciated layer of regulation in the p53 network and may mediate p53-dependent
stress responses and tumor suppressive functions. To address this hypothesis, in Aim 1, we propose to
perform a comprehensive series of experiments at the cellular level, which will test whether genetic inhibition of
lncRNA-Gadd45g and Pvt1alt in primary and transformed cell lines affects p53-dependent transcriptional and
cellular responses to stress. In parallel, we will examine whether genetic inhibition of the two lncRNAs in
developing tumors in a mouse model of lung cancer promotes tumor development, as shown for p53. Together,
this set of experiments will establish the physiological relevance of cis-regulatory lncRNAs in the context of the
p53 network in vitro and in vivo. In Aims 2 and 3, we will elucidate the mechanism of action of lncRNA-
Gadd45g and Pvt1alt. Aim 2 applies an innovative genetic approach for transcript-specific degradation,
developed by us, in order to determine the functional element of cis-regulation by dissociating the
accumulation of the lncRNA transcript from the act of its transcription and from the underlying DNA elements in
the locus. Findings from this set of studies will advance the field by clarifying a controversy about the central
player in local gene expression control and may elucidate how cis-regulatory relationships become disrupted in
disease states, including cancer. Finally, in an effort to define universal principles as well as locus-specific
features of cis regulation, in Aim 3, we will determine whether cis-acting lncRNAs impact local transcriptional
and epigenetic events by examining the kinetics of transcription, the epigenetic state, and the chromatin
architecture in their respective loci. In summary, the studies proposed here take advantage of rigorous genetic
approaches, elegant functional assays, and state-of-the art molecular tools to address the contribution of cis-
regulatory lncRNAs to the p53 tumor suppressor pathway. The broad...

## Key facts

- **NIH application ID:** 10153726
- **Project number:** 5R37CA230580-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nadya M Dimitrova
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $359,545
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153726

## Citation

> US National Institutes of Health, RePORTER application 10153726, Roles and mechanisms of cis-regulatory IncRNAs in the p53 tumor suppressor pathway (5R37CA230580-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153726. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*