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Single-Cell RNA-Sequencing-Based CRISPRi Screening Resolves Molecular Drivers of Early Human Endoderm Development.

Abstract：

:Studies in vertebrates have outlined conserved molecular control of definitive endoderm (END) development. However, recent work also shows that key molecular aspects of human END regulation differ even from rodents. Differentiation of human embryonic stem cells (ESCs) to END offers a tractable system to study the molecular basis of normal and defective human-specific END development. Here, we interrogated dynamics in chromatin accessibility during differentiation of ESCs to END, predicting DNA-binding proteins that may drive this cell fate transition. We then combined single-cell RNA-seq with parallel CRISPR perturbations to comprehensively define the loss-of-function phenotype of those factors in END development. Following a few candidates, we revealed distinct impairments in the differentiation trajectories for mediators of TGFβ signaling and expose a role for the FOXA2 transcription factor in priming human END competence for human foregut and hepatic END specification. Together, this single-cell functional genomics study provides high-resolution insight on human END development.

journal_name

Cell Rep

journal_title

Cell reports

authors

Genga RMJ,Kernfeld EM,Parsi KM,Parsons TJ,Ziller MJ,Maehr R

doi

10.1016/j.celrep.2019.03.076

subject

Has Abstract

pub_date

2019-04-16 00:00:00

pages

708-718.e10

issue

3

issn

2211-1247

pii

S2211-1247(19)30406-1

journal_volume

27

pub_type

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