Parallel functional assessment of m6A sites in human endodermal differentiation with base editor screens

Weisheng Cheng, Fang Liu, Zhijun Ren, Wenfang Chen, Yaxin Chen, Tianwei Liu, Yixin Ma, Nan Cao () and Jinkai Wang ()
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Weisheng Cheng: Sun Yat-sen University
Fang Liu: the First Affiliated Hospital of Anhui Medical University
Zhijun Ren: Sun Yat-sen University
Wenfang Chen: Sun Yat-sen University
Yaxin Chen: Sun Yat-sen University
Tianwei Liu: Sun Yat-sen University
Yixin Ma: Sun Yat-sen University
Nan Cao: Sun Yat-sen University
Jinkai Wang: Sun Yat-sen University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract N6-methyladenosine (m6A) plays important role in lineage specifications of embryonic stem cells. However, it is still difficult to systematically dissect the specific m6A sites that are essential for early lineage differentiation. Here, we develop an adenine base editor-based strategy to systematically identify functional m6A sites that control lineage decisions of human embryonic stem cells. We design 7999 sgRNAs targeting 6048 m6A sites to screen for m6A sites that act as either boosters or barriers to definitive endoderm specification of human embryonic stem cells. We identify 78 sgRNAs enriched in the non-definitive endoderm cells and 137 sgRNAs enriched in the definitive endoderm cells. We successfully validate two definitive endoderm promoting m6A sites on SOX2 and SDHAF1 as well as a definitive endoderm inhibiting m6A site on ADM. Our study provides a functional screening of m6A sites and paves the way for functional studies of m6A at individual m6A site level.

Date: 2022
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DOI: 10.1038/s41467-022-28106-0

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