Decoding the role of chromatin architecture in alveolar epithelial cell identity and disease

About This Grant

Project Abstract The alveolar epithelium is composed of two distinct cell types—alveolar epithelial type I (AT1) cells, which facilitate gas exchange, and alveolar epithelial type II (AT2) cells, which act as progenitors for AT1 cells. Successful lung repair following alveolar injuries requires AT2 cell proliferation and differentiation into AT1 cells, a process that involves the restructuring of gene regulatory networks and cell-type specific chromatin landscapes that underly these two cell fates. A dysfunctional regenerative response has been observed in a variety of severe lung diseases, involving AT2 cells acquiring a pathologic, alveolar-basal intermediate (ABI) cell state at the expense of an AT1 fate. The mechanisms that facilitate the cell fate decisions involved in AT2 cell maintenance and differentiation are not well understood, which has resulted in a lack of effective treatments to promote alveolar regeneration. This project aims to identify and characterize regulatory, 3-dimensional “hubs” of chromatin interaction that instruct distinct alveolar epithelial cell fates, and to determine how these hubs and their associated transcription factors regulate the acquisition of healthy and disease-associated states. Using human induced pluripotent stem cell (iPSC) models of AT1- and AT2-like cells (iAT1s and iAT2s), we will apply advanced chromatin mapping techniques to identify cell-type specific enhancer-promoter interactions and to characterize chromatin hubs that potentially regulate normal AT1 and AT2 cell identity. In Aim 1, we will map these interactions in healthy iAT1 and iAT2 cells, comparing their chromatin landscapes to pinpoint regulatory hubs that we hypothesize are responsible for cell-type specific gene expression. In Aim 2, we will explore the effects of haploinsufficiency of the lung lineage transcription factor, NKX2-1, on chromatin topology of iAT2 cells, hypothesizing that reduced NKX2-1 expression disrupts normal AT2 cell identity and favors a pathological ABI state. The findings from this research will enhance our understanding of the chromatin-based mechanisms that control lung cell fate decisions and provide insights into how disruptions of chromatin organization contribute to pulmonary disease.