# Unraveling regulatory functions of circRNAs at the muscleblind locus

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2024 · $325,683

## Abstract

PROJECT SUMMARY
Regulation of RNA metabolism is emerging as a major regulatory hub for gene expression control in tissues
like the brain and the muscle, which don’t undergo cell division. Therefore, it is not surprising that there is a
strong link between perturbation of RNA metabolism and a number of muscular and neurodegenerative
diseases including myotonic dystrophy (MD) and amyotrophic lateral dystrophy (ALS). For example, MD- 1
is provoked by the sequestration of the splicing factor MBNL1 encoded by the gene muscleblind-1. MBNL1
and another member of the MBL family (MBNL2) have important and overlapping functions in RNA
processing and transport, in particular in muscle and neurons.
Circular RNAs (circRNAs) are a highly abundant, not well-characterized type of non-coding RNA. These
RNAs are generated by circularization of specific exons, and their functionality is still controversial. Recent
work from my laboratory has demonstrated that circRNA production competes with pre-mRNA splicing,
suggesting that circRNAs are general cis regulators of gene expression. We found by studying of MBL, the
Drosophila homolog of MBNL1, that this protein regulates the production of a subset of circRNAs, including
one generated from its own locus (circMbl). Work from the previous period demonstrated that circRNAs
generated from the mbl locus regulate gene expression, physiology and behavior. We found that these
circRNAs act in cis and are part of a self-regulatory loop that limits MBL expression. In addition, we found
that circMbl has functions in trans as knockdown (KD) of circMbl provokes several developmental,
physiological and behavioral phenotypes which are distinct but related to the ones observed upon MBL KD.
Together, our data demonstrates that circMbl and MBL work in related pathways but have distinct functions.
Here we aim to unravel the molecular and physiological implications of circMbl production and
function. This work will result in pioneering functional characterization of circRNAs in vivo and will be key for
understanding how MBL production and function are regulated in vivo. For doing so we will: identify MBL-
dependent and MBL-independent mechanisms of action of circMbl. We will follow by determining the
physiological and neural roles of mbl and circMbl isoforms. This project will illuminate essential
regulatory mechanisms of mbl expression and function. As or more importantly, this project is both technically
and intellectually innovative in its analysis of the roles of circRNAs in central aspects of physiology, and
behavior. Our project builds on strong preliminary results and the unique and constantly evolving expertise
of our group.

## Key facts

- **NIH application ID:** 10826034
- **Project number:** 2R01GM124406-05A1
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Sebastian Kadener
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $325,683
- **Award type:** 2
- **Project period:** 2017-08-04 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826034

## Citation

> US National Institutes of Health, RePORTER application 10826034, Unraveling regulatory functions of circRNAs at the muscleblind locus (2R01GM124406-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10826034. Licensed CC0.

---

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