Bivalent genes that undergo transcriptional switching identify networks of key regulators of embryonic stem cell differentiation.

BMC Genomics
Ah-Jung Jeon, Greg Tucker-Kellogg

Abstract

Bivalent promoters marked with both H3K27me3 and H3K4me3 histone modifications are characteristic of poised promoters in embryonic stem (ES) cells. The model of poised promoters postulates that bivalent chromatin in ES cells is resolved to monovalency upon differntiation. With the availability of single-cell RNA sequencing (scRNA-seq) data, subsequent switches in transcriptional state at bivalent promoters can be studied more closely. We develop an approach for capturing genes undergoing transcriptional switching by detecting 'bimodal' gene expression patterns from scRNA-seq data. We integrate the identification of bimodal genes in ES cell differentiation with analysis of chromatin state, and identify clear cell-state dependent patterns of bimodal, bivalent genes. We show that binarization of bimodal genes can be used to identify differentially expressed genes from fractional ON/OFF proportions. In time series data from differentiating cells, we build a pseudotime approximation and use a hidden Markov model to infer gene activity switching pseudotimes, which we use to infer a regulatory network. We identify pathways of switching during differentiation, novel details of those pathway, and transcription factor coordination with d...Continue Reading

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Citations

Aug 22, 2021·Stem Cell Reviews and Reports·Han SunLisha Li

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Methods Mentioned

BETA
scRNA-seq
ChIP-seq
FACS
RNA-seq

Software Mentioned

R package Mixtools
R package infotheo
MSigDB “ ”
MSigDB
PST
R package minet
Rtsne
R package diptest
BASiCS
biomaRt

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