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Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming

ABSTRACT: Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming

PROVIDER: PRJNA556313 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9735090_1.fastq.gz	Fastqsanger.gz
	SRR9735090_2.fastq.gz	Fastqsanger.gz
	SRR9735100.fastq.gz	Fastqsanger.gz
	SRR9735110.fastq.gz	Fastqsanger.gz
	SRR9735120_1.fastq.gz	Fastqsanger.gz

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Mitigating Antagonism between Transcription and Proliferation Allows Near-Deterministic Cellular Reprogramming.

Project description:Although cellular reprogramming enables the generation of new cell types for disease modeling and regenerative therapies, reprogramming remains a rare cellular event. By examining reprogramming of fibroblasts into motor neurons and multiple other somatic lineages, we find that epigenetic barriers to conversion can be overcome by endowing cells with the ability to mitigate an inherent antagonism between transcription and DNA replication. We show that transcription factor overexpression induces unusually high rates of transcription and that sustaining hypertranscription and transgene expression in hyperproliferative cells early in reprogramming is critical for successful lineage conversion. However, hypertranscription impedes DNA replication and cell proliferation, processes that facilitate reprogramming. We identify a chemical and genetic cocktail that dramatically increases the number of cells capable of simultaneous hypertranscription and hyperproliferation by activating topoisomerases. Further, we show that hypertranscribing, hyperproliferating cells reprogram at 100-fold higher, near-deterministic rates. Therefore, relaxing biophysical constraints overcomes molecular barriers to cellular reprogramming.

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Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming

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Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming (iMN)

Project description:RNA sequencing analysis of Hb9::GFP mouse embryonic fibroblasts infected with control or reprogramming transcription factors at 4 dpi, and Hb9::GFP+ mouse induced motor neurons generated using transcription factor overexpression. The goal of this study is to examine the transcriptional path of reprogramming cells to identify molecular mechanisms and populations of highly efficient reprogramming.

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