TY - JOUR
T1 - Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data
AU - Zhang, Zidong
AU - Ruf-Zamojski, Frederique
AU - Zamojski, Michel
AU - Bernard, Daniel J.
AU - Chen, Xi
AU - Troyanskaya, Olga G.
AU - Sealfon, Stuart C.
N1 - Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2024/1/25
Y1 - 2024/1/25
N2 - Single same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin ‘peaks’. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.
AB - Single same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin ‘peaks’. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.
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U2 - 10.1093/nar/gkad1166
DO - 10.1093/nar/gkad1166
M3 - Article
C2 - 38084892
AN - SCOPUS:85183472265
SN - 0305-1048
VL - 52
SP - 572
EP - 582
JO - Nucleic acids research
JF - Nucleic acids research
IS - 2
ER -