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

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $344,804

## 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 oncogenic
lncRNA that promotes breast tumor progression and metastasis. MALAT1 is induced during hypoxia, and
regulates the pre-mRNA alternative splicing (AS) of genes involved in hypoxia response. However, the
molecular mechanisms by which MALAT1 controls AS during hypoxia signaling, tumor progression and
metastasis remain to be elucidated. Genome-wide RNA mapping studies reveal that MALAT1 interacts with
transcriptionally active genes and their pre-mRNA. Further, MALAT1 interacts with several members of the
SR-family of splicing factors (SRSFs), and cells with deregulated expression of MALAT1 show defects in
SRSF levels and localization along with aberrant 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, modulates
the binding of SRSFs with their target pre-mRNAs and other speckle resident proteins. 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 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 significance of MALAT1 during in vivo hypoxia
response using 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,
and 2) regulated localization of genes near speckles and AS. The approach is technically innovative,
because it employs state of the art cell biological techniques, including super-resolution imaging and genetic
approaches such as CRISPR/dCasRx-mediated RNA tethering assays. The proposed research is
significant because deciphering the role of MALAT1 in regulating the expression of 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:** 9887679
- **Project number:** 1R01GM132458-01A1
- **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:** 2020
- **Award amount:** $344,804
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9887679

## Citation

> US National Institutes of Health, RePORTER application 9887679, Characterization of nuclear-retained RNA-mediated gene regulatory mechanisms (1R01GM132458-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9887679. Licensed CC0.

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