# R-loops as Mechanisms Governing Neural Differentiation and Cell Type-Specific Transcription

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $29,520

## Abstract

PROJECT SUMMARY
 The neuropsychiatric disorders schizophrenia and autism together affect over 15% of children in the
United States, representing a significant public health concern. Development of effective therapeutics and
diagnostic tools for these disorders has been hindered by our incomplete understanding of their complex
neurodevelopmental etiologies. Gene expression variation is a common attribute of these disorders, thought to
arise from developmental stage- and tissue-specific RNA regulation during neurodevelopment. New genome-
wide mapping strategies have identified a connection between R-loops (a three-stranded nucleic acid structure
containing a DNA/RNA hybrid) and transcriptional regulation, suggesting a possible link between R-loops and
gene expression variation. However, R-loops have never before been characterized on a genome-wide scale in
the human brain, precluding research studying their role in neurodevelopmental illnesses. Our research has
showed that R-loops may poise developmental genes for transcription during neural differentiation, and our
immediate goal is to test this hypothesis by leveraging human induced pluripotent stem cell (hiPSC)-based
models to functionally manipulate R-loop levels. Specifically, we aim to reduce R-loop levels in hiPSC-derived
neural progenitor cells and measure the effect this has on transcription, differentiation, and ability of neural cells
to form functional synapses. We aim to identify a causal mechanism of this R-loop-mediated transcriptional
poising by exploring the hypothesis that R-loops stall RNA polymerase II, as stalled RNA polymerase II is thought
to keep developmental genes transcriptionally inactive but ready for expression upon developmental cues.
Importantly, we will map R-loops genome-wide for the first time in the developing human brain, and link R-loop
distributional shifts during human neurogenesis with neurodevelopmental disease-associated gene expression
signatures. Here, we will use cutting-edge techniques, including DNA/RNA immunoprecipitation followed by next-
generation sequencing, to achieve these goals. These first steps toward understanding R-loop function in neural
cells will facilitate our long-term objective to uncover the epigenetic mechanisms of aberrant RNA regulation in
neuropsychiatric illness, in order to improve diagnostics and identify novel therapeutic targets for these illnesses.

## Key facts

- **NIH application ID:** 10118038
- **Project number:** 5F31MH121062-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Elizabeth Ann LaMarca
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118038

## Citation

> US National Institutes of Health, RePORTER application 10118038, R-loops as Mechanisms Governing Neural Differentiation and Cell Type-Specific Transcription (5F31MH121062-02). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10118038. Licensed CC0.

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