Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.

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
Dev Cell. 2019 48 (1): 49-63.e7

PMID: 30620902 · PMCID: PMC6327977 · DOI:10.1016/j.devcel.2018.11.048

In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; 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., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β 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.

Published by Elsevier Inc.

MeSH Terms (13)

Animals Basic Helix-Loop-Helix Transcription Factors Cell Differentiation Cell Lineage Endocrine Cells Homeodomain Proteins Insulin-Secreting Cells Islets of Langerhans Mice Nerve Tissue Proteins Organogenesis Pancreas Transcription Factors

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