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DOT1L regulates lung developmental epithelial cell fate and adult alveolar stem cell differentiation after acute injury.

ABSTRACT: AT2 cells harbor alveolar stem cell activity in the lung and can self-renew and differentiate into AT1 cells during homeostasis and after injury. To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors. This screen identified DOT1L as a regulator of AT2 cell growth and differentiation. In vivo inactivation of Dot1l leads to precocious activation of both AT1 and AT2 gene expression during lung development and accelerated AT1 cell differentiation after acute lung injury. Single-cell transcriptome analysis reveals the presence of a new AT2 cell state upon loss of Dot1l, characterized by increased expression of oxidative phosphorylation genes and changes in expression of critical transcription and epigenetic factors. Taken together, these data demonstrate that Dot1l controls the rate of alveolar epithelial cell fate acquisition during development and regeneration after acute injury.

SUBMITTER: Li S

PROVIDER: S-EPMC10545485 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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DOT1L regulates lung developmental epithelial cell fate and adult alveolar stem cell differentiation after acute injury.

Li Shanru S Liberti Derek D Zhou Su S Ying Yun Y Kong Jun J Basil Maria C MC Cardenas-Diaz Fabian L FL Shiraishi Kazushige K Morley Michael P MP Morrisey Edward E EE

Stem cell reports 20230817 9

AT2 cells harbor alveolar stem cell activity in the lung and can self-renew and differentiate into AT1 cells during homeostasis and after injury. To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors. This screen identified DOT1L as a regulator of AT2 cell growth and differentiation. In vivo inactivation of Dot1l leads to precocious activation of both AT1 and AT2 gene ex ...[more]

PMID: 37595582

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Project description:Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK)14+/18-] and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1 d/d). Interestingly, corn oil (CO) vehicle-treated Six1 d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wild-type Six1 (Six1 +/+) mice. Furthermore, Six1 d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1 +/+ mice. Although DES Six1 d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1 +/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14+/18+ cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14+/18+ cells. In human endometrial biopsies, 35% of malignancies showed CK14+/18+ expression, which positively correlated with tumor stage and grade and was not present in normal endometrium. IMPLICATIONS: Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14+/18+ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.

Dataset Information

DOT1L regulates lung developmental epithelial cell fate and adult alveolar stem cell differentiation after acute injury.

Publications

DOT1L regulates lung developmental epithelial cell fate and adult alveolar stem cell differentiation after acute injury.

Similar Datasets

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