# Role of noncoding RNA decay in glucose homeostasis

> **NIH NIH K01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $40,641

## Abstract

Project Summary/Abstract
Regulation of RNA biogenesis and decay is critical for cellular homeostasis and dysregulation in these
processes leads to a variety of human developmental and metabolic disorders. While the transcriptional
regulation of RNA expression has been widely studied, the importance of RNA decay is only beginning
to be appreciated. Specifically, studying the regulation of noncoding RNA (ncRNA) expression and
decay is hampered due to limitations caused by their size, abundance, modifications, and/or structural
complexities. We have recently identified a 3’-to-5’ exoribonuclease enzyme, Dis3l2, as a major player
in ncRNA decay. In that study, I performed a global identification of Dis3l2 substrates and found that
the majority of Dis3l2 targets are ncRNAs. This led to our identification of DIS3L2-Mediated Decay
(DMD) as a quality control pathway that ensures the fidelity of ncRNAs. Germline mutations in human
DIS3L2 gene have been linked to the Perlman syndrome that is a rare but devastating disorder
associated with early lethality, hypoglycemia, kidney abnormalities, and hyperplasia in pancreas. These
suggest that dysregulated ncRNA decay in Dis3l2-depleted patients disrupts metabolic homeostasis.
The main aim of this research project is to unravel how Dis3l2 deficiency leads to the impaired function
of metabolic organs remains unknown. To understand the role of ncRNA decay in metabolism and
specially in glucose homeostasis, I plan to combine several innovative approaches to investigate the
molecular and physiological functions of Dis3l2 enzyme using in vitro and in vivo systems. I have
identified the 7SL RNA component of the signal recognition particle (SRP), a critical player in
endoplasmic reticulum (ER)-mediated translation, as a major substrate of Dis3l2. I discovered that in
the absence of Dis3l2, aberrant 7SL RNAs accumulate in the cells and perturb ER-mediated protein
translation. We have generated a Dis3l2 knockout (KO) mouse model of Perlman syndrome that
manifests the main symptoms of human patients including perinatal lethality, kidney overgrowth,
abrogated regulation of blood glucose and insulin secretion. Moreover, Dis3l2 depletion caused
impaired ER-translation, ER-calcium homeostasis and insulin secretion in vitro. This proves a direct
role of Dis3l2 in regulation of insulin secretion in response to glucose stimulation. I will utilize Dis3l2 KO
mouse model to further determine the effect of impaired ER-mediated protein translation on cellular
and organism physiology. My hypothesis is that Dis3l2 depletion impairs homeostatic ER-associated
protein translation due to an accumulation of aberrant 7SL RNAs. This proposal is innovative because
the involvement of the Dis3l2-mediated ncRNA decay in glucose homeostasis has not been previously
reported. Successful completion of this proposal has broad implications in understanding the basis of
glucose homeostasis and have a significant impact on the development of treatments f...

## Key facts

- **NIH application ID:** 10135053
- **Project number:** 5K01DK121861-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Mehdi Pirouz
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,641
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135053

## Citation

> US National Institutes of Health, RePORTER application 10135053, Role of noncoding RNA decay in glucose homeostasis (5K01DK121861-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135053. Licensed CC0.

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