# Role of the bHLH Transcription Factor ASCL1 in Central Tolerance

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $286,636

## Abstract

Project Summary/Abstract
This proposal’s objective is to determine whether genetic mutations that alter the transcriptional activity of the
basic helix-loop-helix (bHLH) transcription factor Achaete-scute complex 1 (ASCL1) contribute to the etiology
of organ-specific autoimmunity in humans. Transcription factor mutations that result in the misregulation of
gene expression are particularly potent drivers of human disease. Studies of individuals and families with
suspected monogenic forms of autoimmunity provide a unique opportunity to understand novel pathways in
human immune biology and have revealed mutations in thymic transcription factors as potent drivers of
autoimmunity. For example, mutations in the Autoimmune Regulator (AIRE) gene cause a spectrum of organ-
specific autoimmune conditions such as hypoparathyroidism, hypothyroidism, Addison’s disease (adrenals)
and type 1 diabetes (pancreas). AIRE is a transcriptional activator that drives the expression of tissue-
restricted self-antigens (TSAs) in medullary thymic epithelial cells (mTECs) to enable the deletion of
autoreactive T cells, a process termed “central tolerance”. While AIRE is critical for central tolerance, the
severity and spectrum of organ-specific clinical disease among AIRE patients, including siblings with identical
AIRE mutations, underscores the existence of disease-modulating variables, including perhaps organ-specific
disease-promoting and/or ameliorating genetic elements that modulate AIRE expression, activity or function.
ASCL1, an established bHLH transcription factor that orchestrates the proliferation, specification and
differentiation of neural progenitors, was recently reported to be expressed in three human medullary thymic
cell subpopulations: two known to be critical for central tolerance, 1) AIRE+ mTECs and 2) their developmental
precursors (AIRE- mTECs); and 3) a novel subpopulation of thymic neuroendocrine cells. The role of ASCL1 in
immune biology and autoimmune disease is completely unknown. We have also identified one individual and
two siblings in our UCSF patient registry with suspected monogenic autoimmunity and ASCL1 mutations. The
individuals tested negative for known genetic causes of autoimmunity and have rare/predicted deleterious
ASCL1 mutations that are adjacently positioned within the transactivation domain of the protein. The novel
discovery of ASCL1 expression in the thymus coupled with the identification of suspected ASCL1 monogenic
autoimmune patients leads to the general hypothesis for this project. We hypothesize that ASCL1 mutations
that alter its transcriptional activity disrupt the development, function, and/or microenvironment of AIRE+
mTECs, resulting in autoimmunity.

## Key facts

- **NIH application ID:** 10953466
- **Project number:** 1R21AI185776-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Michael S German
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $286,636
- **Award type:** 1
- **Project period:** 2024-06-13 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10953466

## Citation

> US National Institutes of Health, RePORTER application 10953466, Role of the bHLH Transcription Factor ASCL1 in Central Tolerance (1R21AI185776-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10953466. Licensed CC0.

---

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