# Mechanisms of Cell-type-specific pre-mRNA Splicing

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2024 · $466,828

## Abstract

Mechanisms of Cell-type-specific pre-mRNA Splicing
Abstract:
The overarching goal of this project is to uncover cis- and trans-regulatory mechanisms of pre-mRNA splicing at
the cell-type level. While single-cell RNA Sequencing (scRNA-Seq) is revolutionizing our understanding of cell-
type heterogeneity in animal tissues, the extent and mechanism of cell-type-specific splicing remain largely
uncharted. The major challenges are threefold: 1) Current scRNA-Seq platforms are predominantly built on read
counts of the 3’ or 5’ end fragments of polyadenylated RNAs and do not have sufficient coverage for splice
junctions; 2) Homologous RNA binding proteins (RBPs) frequently have overlapping expression patterns and
redundant functions, making it challenging to uncover their full functions in vivo; and 3) Protein-RNA interaction
has been predominantly studied in cell lines or bulk tissues using UV-crosslinking and immunoprecipitation-
based approaches, and it remains a challenge to identify RBP targets in specific cell types from intact tissues.
My group uses the mouse brain as a model system and has been developing new tools to overcome these
challenges. We have made proof-of-concept progress and seek to 1) uncover cis-regulatory elements and
coordinated splicing patterns by single-cell long-read sequencing; 2) study redundant RBP functions by
multiplexed genome editing; and 3) investigate protein-RNA interaction at the cell-type level by dual RNA-
deaminase editing and sequencing. Successful completion of this project will generate new tools and datasets
to understand the mechanisms of cell-type-specific pre-mRNA processing. The MIRA funding mechanism will
permit the flexibility to integrate technological advances and study new biological questions.

## Key facts

- **NIH application ID:** 10765269
- **Project number:** 1R35GM152177-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Xiaochang Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,828
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765269

## Citation

> US National Institutes of Health, RePORTER application 10765269, Mechanisms of Cell-type-specific pre-mRNA Splicing (1R35GM152177-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10765269. Licensed CC0.

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