Inferring cellular and molecular processes in single-cell data with non-negative matrix factorization using Python, R and GenePattern Notebook implementations of CoGAPS

Johnson, Jeanette A. I.; Tsang, Ashley P.; Mitchell, Jacob T.; Zhou, David L.; Bowden, Julia; Davis-Marcisak, Emily; Sherman, Thomas; Liefeld, Ted; Loth, Melanie; Goff, Loyal A.; Zimmerman, Jacquelyn W.; Kinny-Köster, Ben; Jaffee, Elizabeth M.; Tamayo, Pablo; Mesirov, Jill P.; Reich, Michael; Fertig, Elana J.; Stein-O’Brien, Genevieve L.

doi:10.1038/s41596-023-00892-x

Cited by 4 publications

References 51 publications

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Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys–Dietz syndrome mouse model

Bramel,

Espinoza Camejo,

Creamer

et al. 2024

Nat Cardiovasc Res

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Loeys–Dietz syndrome (LDS) is a connective tissue disorder caused by mutations that decrease transforming growth factor-β signaling. LDS-causing mutations increase the risk of aneurysm throughout the arterial tree, yet the aortic root is a site of heightened susceptibility. Here we investigate the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1 M318R/+ LDS mice by single-cell transcriptomics to identify molecular determinants of this vulnerability. Reduced expression of components of the extracellular matrix–receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4 -expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human single-cell RNA sequencing dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired transforming growth factor-β signaling.

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Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys–Dietz syndrome mouse model

Bramel,

Espinoza Camejo,

Creamer

et al. 2024

Nat Cardiovasc Res

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Cell fate specification and conversion generate foveolar cone subtype patterning in human retinal organoids

Hussey

Eldred

Reh

et al. 2023

Preprint

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The mechanisms that generate patterns of cell types unique to humans are poorly understood. In the central region of the human retina, the high-acuity foveola is notable, in part, for its dense packing of green (M) and red (L) cones and absence of blue (S) cones. To identify mechanisms that promote M/L and suppress S cone patterning in the foveola, we examined human fetal retinas and differentiated human retinal organoids. During development, sparse S-opsin-expressing cones are observed in the foveola initially. Later, the foveola contains a mix of cones that either co-express S- and M/L-opsins or express M/L-opsin only. In adulthood, only M/L cones are present. Two signaling pathway regulators are highly and continuously expressed in the central retina: Cytochrome P450 26 subfamily A member 1 (CYP26A1) that degrades retinoic acid (RA) and Deiodinase 2 (DIO2) that promotes thyroid hormone (TH) signaling. CYP26A1 null mutant organoids and high RA conditions increased S cones and limited M/L cones in human retinal organoids. Sustained TH signaling promoted the generation of M/L-opsin-expressing cones and induced M/L-opsin expression in S-opsin-expressing cones, showing that cone fate is plastic. Our data suggest that early CYP26A1 degrades RA to specify M/L cones and limit S cones and that continuous DIO2 expression sustains high levels of TH to convert S cones into M/L cones, yielding the M/L cone subtype patterning of the foveola. As the foveola is highly susceptible to impairment in diseases such as macular degeneration, a leading cause of vision loss, our findings inform organoid design for potential therapeutic applications.

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Study on personalized medical decision support System based on big data

Luo

2024

Proceedings of the 2024 4th International Conference on Bioinformatics and Intelligent Computing

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Inferring cellular and molecular processes in single-cell data with non-negative matrix factorization using Python, R and GenePattern Notebook implementations of CoGAPS

Cited by 4 publications

References 51 publications

Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys–Dietz syndrome mouse model

Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys–Dietz syndrome mouse model

Cell fate specification and conversion generate foveolar cone subtype patterning in human retinal organoids

Study on personalized medical decision support System based on big data

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