# Characterization of nuclear-retained RNA-mediated gene regulatory mechanisms

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $125,000

## Abstract

Human genome encodes a large number of non-protein coding RNA (ncRNA) genes, including thousands
long ncRNA (lncRNA) genes. MALAT1 is an abundant, conserved and nuclear speckle localized lncRNA
that promotes breast tumor metastasis. MALAT1 is induced several folds during hypoxia, and influences the
pre-mRNA alternative splicing (AS) of genes controlling hypoxia response. However, the molecular
mechanisms by which MALAT1 controls AS during hypoxia signaling remain to be elucidated. Genome-
wide RNA mapping analyses reveal that MALAT1 interacts with transcriptionally active genes and their pre-
mRNA. Further, MALAT1 interacts with several members of the SR-family of pre-mRNA splicing factors
(SRSFs), and cells with deregulated expression of MALAT1 show defects in SRSF-mediated AS. The
objective of the present proposal is to delineate the molecular function of MALAT1 in SRSF-mediated AS,
by utilizing hypoxia response as an experimental model system. The central hypothesis is that MALAT1 by
enriching SRSFs in nuclear speckles, controls the binding of SRSFs with their target pre-mRNAs and other
SRSF interactors. Guided by strong preliminary data, this hypothesis will be tested in the following specific
aims: 1) Determine how MALAT1 regulates SRSF-mediated alternative splicing (AS). 2) Determine the
significance of nuclear speckle enrichment of MALAT1 in pre-mRNA processing. In the first aim, PI will
determine how MALAT1 regulates the binding and recruitment of SRSF1 (a prototypical member of SRSF
proteins) to their target pre-mRNAs in hypoxic breast cancer cells. PI will also determine the involvement of
MALAT1 in AS during in vivo hypoxia response in tumor mouse models. Under the second aim, PI, by using
super-resolution and live imaging studies will determine the involvement of MALAT1 in the, 1) spatial
organization of speckle components, including SRSFs, and 2) regulated localization of genes in speckle
proximity. The approach is technically innovative, because it employs state of the art techniques, including
super-resolution imaging and CRISPR/dCasRx-mediated RNA tethering assays. The proposed research is
significant because deciphering the role of MALAT1 in regulating the expression of hypoxia responsive
genes will have broad translational significance in the context of breast cancer treatment. Ultimately, this
knowledge will pave way to future studies utilizing MALAT1 as a novel therapeutic target against cancer.

## Key facts

- **NIH application ID:** 10379740
- **Project number:** 3R01GM132458-02S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Prasanth Kumar Vijayan Kannanganattu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $125,000
- **Award type:** 3
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379740

## Citation

> US National Institutes of Health, RePORTER application 10379740, Characterization of nuclear-retained RNA-mediated gene regulatory mechanisms (3R01GM132458-02S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10379740. Licensed CC0.

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