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Kinetics of chromatin accessibility during hepatic conversion

ABSTRACT: Kinetics of chromatin accessibility during hepatic conversion

PROVIDER: PRJNA625934 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11561403_1.fastq.gz	Fastqsanger.gz
	SRR11561403_2.fastq.gz	Fastqsanger.gz
	SRR11561404_1.fastq.gz	Fastqsanger.gz
	SRR11561404_2.fastq.gz	Fastqsanger.gz
	SRR11561405_1.fastq.gz	Fastqsanger.gz

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Project description:Recent studies have shown that defined hepatic factors could lead to the direct conversion of fibroblasts into induced hepatocytes (iHeps). However, reported conversion efficiencies are vey low and the underlying mechanism of the hepatic lineage conversion is largely unknown. Here, we report that direct conversion into iHeps is a stepwise transition involving erasure of somatic memory, mesenchymal-to-epithelial transition, and induction of hepatic cell fate in a sequential manner. Throughout screening for additional factors that could potentially enhance the kinetics of the MET and hepatic programs, we have found that c-Myc and Klf4 (CK) dramatically accelerate the conversion kinetics, resulting in remarkably improved generation of iHeps (>87 fold). Furthermore, we identified small molecules that could replace the roles of CK and thus led to the highly efficient generation of iHeps without CK. Finally, we show that a single factor (Hnf1α) supported by small molecules is sufficient to robustly induce transprogramming of fibroblasts into functional hepatocyte-like cells with high yield. This novel approach might help to fully elucidate the direct conversion process and also facilitate the translation of iHep into clinic.

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