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Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing
Pancreatic Progenitor Identity.
Authors Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi
PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
Submitted By Submitted Externally on 1/25/2019
Status Published
Journal Developmental cell
Year 2019
Date Published 1/1/2019
Volume : Pages 48 : 49 - 63.e7
PubMed Reference 30620902
Abstract In the developing pancreas, transient Neurog3-expressing progenitors give rise
to four major islet cell types: a, ß, d, and ?; when and how the Neurog3+ cells
choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and
combinatorial lineage tracing, we showed here that the Neurog3+ cells
co-expressing Myt1 (i.e., Myt1+Neurog3+) were biased toward ß cell fate, while
those not simultaneously expressing Myt1 (Myt1-Neurog3+) favored a fate. Myt1
manipulation only marginally affected a versus ß cell specification, suggesting
Myt1 as a marker but not determinant for islet-cell-type specification. The
Myt1+Neurog3+ cells displayed higher Dnmt1 expression and enhancer methylation
at Arx, an a-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors
promoted a cell specification, while Dnmt1 overexpression or Arx enhancer
hypermethylation favored ß cell production. Moreover, the pancreatic progenitors
contained distinct Arx enhancer methylation states without transcriptionally
definable sub-populations, a phenotype independent of Neurog3 activity. These
data suggest that Neurog3-independent methylation on fate-determining gene
enhancers specifies distinct endocrine-cell programs.


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