# Regulating transcription of the key pulmonary neuroendocrine lineage driver ASCL1

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $245,250

## Abstract

The bHLH transcription factor ASCL1 (HASH1/MASH1) is essential for specification of the
neuroendocrine (NE) lineage in the lung. NE cells are rare in pulmonary epithelium but they are
thought to play diverse roles during lung development and homeostasis. Increases in NE cell
number have been documented in many lung diseases in children and adults. ASCL1 function is
balanced with NOTCH signaling to control progenitor proliferation and NE differentiation versus
other cell types in the lung. Consistent with the role of ASCL1 as a lineage-specifying factor and
in expanding progenitor populations, ASCL1 has been found to be a lineage-dependent
oncogene in pulmonary NE tumors as well. With these important functions attributed to ASCL1,
and its requirement for controlled spatial and temporal expression during development and in
conditions of lung damage, it is surprising how little is known about regulation of ASCL1 gene
transcription. This gap in knowledge reflects past technical challenges in identifying and
manipulating cis-regulatory elements (REs) found at large distances from the gene of interest, in
addition to challenges of poor culture systems reflecting this NE population and the low fraction
of NE cells in embryonic and adult lungs. REs functioning at long-distances to control key
developmental genes are being discovered using advances in technologies that can interrogate
and manipulate the spatial genome. Here we will exploit these technologies to gain much
needed insights into transcriptional control of ASCL1 using newly reported protocols for
generating pulmonary NE cells from human iPSCs and leveraging cell culture models of
neuroendocrine cancer that express high levels of ASCL1. Each model has a particular strength
that allows unique aspects of ASCL1 regulation to be uncovered. Aims include identifying and
testing functions of long-range REs controlling ASCL1 during NE differentiation in the two
models. Success in these aims will provide functional non-coding regulatory sequences
controlling ASCL1 expression, and presumably, the NE lineage in lung development and
homeostasis. This is important for future projects to identify molecular components of the
signaling complexes working through these REs to reach the goal of providing an understanding
of how a key lineage defining transcriptional regulator is controlled during development and
disease.

## Key facts

- **NIH application ID:** 10143016
- **Project number:** 1R21HD104361-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jane E Johnson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,250
- **Award type:** 1
- **Project period:** 2020-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143016

## Citation

> US National Institutes of Health, RePORTER application 10143016, Regulating transcription of the key pulmonary neuroendocrine lineage driver ASCL1 (1R21HD104361-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143016. Licensed CC0.

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