Deciphering regulatory protein activity in human pancreatic islets via reverse engineering of single-cell sequencing data
Yumi Imai
Yumi Imai
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e154482. https://doi.org/10.1172/JCI154482.
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Commentary

Deciphering regulatory protein activity in human pancreatic islets via reverse engineering of single-cell sequencing data

Abstract

The loss of functional β cell mass contributes to development and progression of type 2 diabetes (T2D). However, the molecular mechanisms differentiating islet dysfunction in T2D from nondiabetic states remain elusive. In this issue of the JCI, Son et al. applied reverse engineering to obtain the activity of gene expression regulatory proteins from single-cell RNA sequencing data of nondiabetic and T2D human islets. The authors identify unique patterns of regulatory protein activities associated with T2D. Furthermore, BACH2 emerged as a potential transcription factor that drives activation of T2D-associated regulatory proteins in human islets.

Authors

Yumi Imai

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Figure 1

Reverse engineering of single-cell RNA sequencing data profiles regulatory protein activity in human islet cells.

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Reverse engineering of single-cell RNA sequencing data profiles regulato...
The activity of regulatory proteins in each human islet cell changes, depending on factors such as cell identity (α vs. β cells) and disease status (nondiabetic [non-DM] vs. T2D). Son, Ding, et al. (7) used reverse engineering to extrapolate the activity of each regulatory protein from the expression level of target genes. Gene expression profiles were obtained by scRNA-Seq analysis, and regulatory protein activity was predicted using two algorithms, ARACNe and metaVIPER. Metabolically inflexible (MI) β cells showed transcription factor (TF) and co-TF activity changes, as exemplified in this model by increases in PPARγ and FOXO1 activities in T2D islets. Notably, BACH2 was implicated as one driver of T2D regulatory protein activities.