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Transcription factor antagonism regulates heterogeneity in embryonic stem cell states

ABSTRACT: Transcription factor antagonism regulates heterogeneity in embryonic stem cell states

PROVIDER: PRJNA714958 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR13981600_1.fastq.gz	Fastqsanger.gz
	SRR13981600_2.fastq.gz	Fastqsanger.gz
	SRR13981601_1.fastq.gz	Fastqsanger.gz
	SRR13981601_2.fastq.gz	Fastqsanger.gz

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Transcription factor antagonism regulates heterogeneity in embryonic stem cell states

Project description:Gene expression heterogeneity underlies the formation of cell states, and switching between states contributes to developmental robustness. While gene expression variation can arise from stochastic transcriptional processes, whether it can be regulated and coordinated by an underlying program is unclear. We characterize the regulatory program underlying heterogeneity and switching between murine embryonic stem cell (mESC) states. Using nascent transcriptome assays, we identified a subset of differentially active and transcribed enhancers (DATEs) across states. DATEs regulate variably expressed gene targets and contribute to cell state formation. Further, DATEs are distinguished by co-binding of Kruppel-like transcription factors Klf4 and Zfp281. In contrast to other transcription factors that form a positive feedback network stabilizing ES cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of their ability to bind DATEs dampens variation in gene expression and reduces heterogeneity. Single cell analysis reveals competing Klf4 and Zfp281 gene programs that define mESC state, consistent with a model whereby Klf4 and Zfp281 generate transcriptional heterogeneity through functional antagonism at DATEs. These results show how antagonistic circuits of TFs and enhancers contributes to gene expression variation and cell state, with potential implications for the generation of diverse cell types during mammalian development.

2022-11-21 | GSE169044 | GEO

Transcription factor antagonism regulates heterogeneity in embryonic stem cell states.

Project description:Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.

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