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Image-derived models of cell organization changes during differentiation and drug treatments.

ABSTRACT: PC12 cells are a popular model system to study changes driving and accompanying neuronal differentiation. While attention has been paid to changes in transcriptional regulation and protein signaling, much less is known about the changes in organization that accompany PC12 differentiation. Fluorescence microscopy can provide extensive information about these changes, although it is difficult to continuously observe changes over many days of differentiation. We describe a generative model of differentiation-associated changes in cell and nuclear shape and their relationship to mitochondrial distribution constructed from images of different cells at discrete time points. We show that the model accurately represents complex cell and nuclear shapes and learn a regression model that relates cell and nuclear shape to mitochondrial distribution; the predictive accuracy of the model increases during differentiation. Most importantly, we propose a method, based on cell matching and interpolation, to produce realistic simulations of the dynamics of cell differentiation from only static images. We also found that the distribution of cell shapes is hollow: most shapes are very different from the average shape. Finally, we show how the method can be used to model nuclear shape changes of human-induced pluripotent stem cells resulting from drug treatments.

SUBMITTER: Ruan X

PROVIDER: S-EPMC7202072 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Image-derived models of cell organization changes during differentiation and drug treatments.

Ruan Xiongtao X Johnson Gregory R GR Bierschenk Iris I Nitschke Roland R Boerries Melanie M Busch Hauke H Murphy Robert F RF

Molecular biology of the cell 20191127 7

PC12 cells are a popular model system to study changes driving and accompanying neuronal differentiation. While attention has been paid to changes in transcriptional regulation and protein signaling, much less is known about the changes in organization that accompany PC12 differentiation. Fluorescence microscopy can provide extensive information about these changes, although it is difficult to continuously observe changes over many days of differentiation. We describe a generative model of diffe ...[more]

PMID: 31774723

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Project description:Objective: It has been demonstrated that the transcription factors TAZ (transcriptional coactivator with PDZ-binding motif), paired box gene 8 (PAX8), and NK2 homeobox 1 (NKX2-1) are coexpressed in the nucleus of thyroid cells. Furthermore, TAZ is known to enhance the transcriptional activity of PAX8 and NKX2-1 as well as the key thyroid-specific gene, thyroglobulin (TG), suggesting a critical role for TAZ in the control of thyroid cell speciation. We previously reported that the small molecule ethacridine, identified as a TAZ activator, was able to induce thyroid-specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells using activin A. Since transcription factors are epigenetically regulated in cell differentiation, we investigated the epigenetic changes in the promoter regions of these key transcription factors during in vitro differentiation of hES cells into thyrocytes. Methods: We initially profiled chromatin accessibility using the technique of Assay for Transposase Accessible Chromatin sequencing (ATAC-seq), and then examined DNA methylation and histone acetylation in the promoter regions of the three selected thyroid transcription factors and the thyroid-specific genes during hES cell differentiation. Results: ATAC-seq analysis showed enriched chromatin accessibility of TAZ, NKX2-1, and PAX8 after exposure to activin A and ethacridine. There were no methylation changes found in the NKX2-1, PAX8, and TAZ promoters by bisulfite sequencing. In contrast, acetylation of histone H4, specifically acetylation of lysine 16, was observed in each of the promoters when measured by chromatin immunoprecipitation polymerase chain reaction assays, which correlated with the activity and expression of NKX2-1 and PAX8 as well as sodium/iodide symporter, thyroid stimulating hormone receptor, and TG genes. Conclusions: These results indicate that ethacridine treatment of activin A-derived endodermal hES cells leads to enhanced chromatin accessibility, which, in turn, allows histone H4 acetylation in the regulation of active genes for speciation of thyroid follicular cells from hES cells.

Dataset Information

Image-derived models of cell organization changes during differentiation and drug treatments.

Publications

Image-derived models of cell organization changes during differentiation and drug treatments.

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