Dataset Information

Transcriptomic Atlas of Embryonic Human Craniofacial Development

ABSTRACT: A majority of craniofacial development occurs early in pregnancy and to fully understand how craniofacial defects arise, it is essential to observe gene expression during this critical time period. To address this, we performed bulk and single-cell RNA-seq on human craniofacial tissue from embryonic development -4 to 8 weeks post conception. To observe how genes are organized in this system, we have constructed co-expression networks from the bulk RNA-seq. Strong disease candidates are likely genes that are co-expressed with many other genes, serving as regulatory hubs within these networks. We have identified 29 modules of co-expressed genes and ~1800 hub genes and found enrichment of craniofacial relevant biology suggesting that these networks could reveal new disease genes and potential targets of previously identified disease genes. We leveraged large functional genomics databases including GTEx and GnomAD to reveal genes that are specifically expressed in craniofacial tissue. We integrate these data with our co-expression networks in order to prioritize the genes in this study. Our analysis revealed 268 novel or underappreciated disease candidate genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197513 | GEO | 2023/06/26

REPOSITORIES: GEO

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Project description:Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n=6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, nucleus, and other membrane-bound organelles. Fourteen of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.

Dataset Information

Transcriptomic Atlas of Embryonic Human Craniofacial Development

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