# Investigating non-coding RNA 7SK in Huntington's Disease neurodegeneration using direct neuronal conversion

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2022 · $32,686

## Abstract

PROJECT SUMMARY
Aging is the greatest risk factor across neurodegenerative diseases and should be recapitulated in adult-onset
disease research models. However, current models utilize human neurons differentiated from induced
pluripotent stem cells, which erase cellular signatures of aging. The Yoo Laboratory has pioneered a system
that uses ectopic expression of microRNAs-9/9* and -124 (miR-9/9*-124) to directly convert human adult
fibroblasts (HAFs) into microRNA-induced neurons (miNs). The miNs maintain molecular age-associated
properties, including the epigenetic clock, telomere lengths and oxidative stress signatures. Additional
transcription factors can synergize with miR-9/9*-124 to generate neuronal cell subtypes including microRNA-
induced medium spiny neurons (MSNs), the primary cells lost in Huntington’s Disease (HD). These subtypes
can model cellular pathologies in adult-onset neurodegenerative disease, such as endogenous aggregation,
DNA damage, mitochondrial dysfunction, and cell death. Degenerating neurons in multiple disorders, including
HD, also demonstrate increased long gene expression (LGE), chromatin dysregulation, and hyperexcitability in
comparison to healthy neurons, yet these HD-associated features have not been successfully targeted for
treatment. This proposal builds on my published first-author study showing that the small nuclear RNA RN7SK
(7SK) is required for neuronal chromatin accessibility and transcription activation across the genome during
miR-9/9*-124 mediated reprogramming. A substantial portion of these neuronal loci and LGE correspond to
genes that are dysregulated in HD-MSNs compared to control MSNs. Here, I propose to use my previous
findings to study how depletion of 7SK expression in HD-MSNs can possibly improve HD neurodegenerative
phenotypes. In Aim 1, I plan to test if knocking down 7SK can bring LGE in HD-MSNs to control levels and if it
can modulate HD-associated chromatin signatures. Following in Aim 2, I propose to assess if repression of
7SK can ameliorate HD-associated neurodegenerative phenotypes, including hyperexcitability, metabolic
dysfunction, and spontaneous cell death. Combining molecular, genomic, electrophysiological, and cell
pathology assays, I will evaluate if reduction of 7SK can restore these HD-associated molecular features and
cellular phenotypes to healthy control MSN levels. Completion of these aims will reveal implications of
neuronal chromatin and transcriptional regulation for alleviating HD-associated phenotypes. These data will
provide foundational knowledge for the advancement of adult-onset neurodegenerative disease modeling and
explore putative epigenomic targets for HD therapeutic development.

## Key facts

- **NIH application ID:** 10464155
- **Project number:** 1F31NS124128-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kitra L Cates
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,686
- **Award type:** 1
- **Project period:** 2022-06-01 → 2023-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464155

## Citation

> US National Institutes of Health, RePORTER application 10464155, Investigating non-coding RNA 7SK in Huntington's Disease neurodegeneration using direct neuronal conversion (1F31NS124128-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464155. Licensed CC0.

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