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A Loss of Function Screen of Epigenetic Modifiers and Splicing Factors during Early Stage of Cardiac Reprogramming. Stem Cells Int 2018;2018:3814747

Date

05/11/2018

Pubmed ID

29743891

Pubmed Central ID

PMC5878887

DOI

10.1155/2018/3814747

Scopus ID

2-s2.0-85056141313   13 Citations

Abstract

Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) is a newly emerged promising approach for cardiac regeneration, disease modeling, and drug discovery. However, its potential has been drastically limited due to the low reprogramming efficiency and largely unknown underlying molecular mechanisms. We have previously screened and identified epigenetic factors related to histone modification during iCM reprogramming. Here, we used shRNAs targeting an additional battery of epigenetic factors involved in chromatin remodeling and RNA splicing factors to further identify inhibitors and facilitators of direct cardiac reprogramming. Knockdown of RNA splicing factors Sf3a1 or Sf3b1 significantly reduced the percentage and total number of cardiac marker positive iCMs accompanied with generally repressed gene expression. Removal of another RNA splicing factor Zrsr2 promoted the acquisition of CM molecular features in CFs and mouse embryonic fibroblasts (MEFs) at both protein and mRNA levels. Moreover, a consistent increase of reprogramming efficiency was observed in CFs and MEFs treated with shRNAs targeting Bcor (component of BCOR complex superfamily) or Stag2 (component of cohesin complex). Our work thus reveals several additional epigenetic and splicing factors that are either inhibitory to or required for iCM reprogramming and highlights the importance of epigenetic regulation and RNA splicing process during cell fate conversion.

Author List

Zhou Y, Alimohamadi S, Wang L, Liu Z, Wall JB, Yin C, Liu J, Qian L

Author

Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin