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

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 Neuro...

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Bibliographic Details
Published in:Developmental cell 2019-01, Vol.48 (1), p.49-63.e7
Main Authors: Liu, Jing, Banerjee, Amrita, Herring, Charles A., Attalla, Jonathan, Hu, Ruiying, Xu, Yanwen, Shao, Qiujia, Simmons, Alan J., Dadi, Prasanna K., Wang, Sui, Jacobson, David A., Liu, Bindong, Hodges, Emily, Lau, Ken S., Gu, Guoqiang
Format: Article
Language:English
Subjects:
Animals
Arx
azacytidine
Basic Helix-Loop-Helix Transcription Factors - metabolism
Cell Differentiation - genetics
Cell Differentiation - physiology
Cell Lineage - physiology
combinatorial lineage tracing
diabetes
DMR
DNA methylation
DNMT
Endocrine Cells - metabolism
epigenetics
glucagon
HMR
Homeodomain Proteins - metabolism
insulin
Insulin-Secreting Cells - metabolism
Islets of Langerhans - cytology
lineage priming
Mice
Myt1
Nerve Tissue Proteins - metabolism
Organogenesis - physiology
p-Creode
Pancreas - metabolism
pseudotime
single-cell RNA-seq
specification
stochastic gene expression
trajectory
Transcription Factors - metabolism
transcriptional noise
α cell
β cell
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Summary: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., Myt1+Neurog3+) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1-Neurog3+) 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 Myt1+Neurog3+ 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. •Neurog3-null cells have distinct DNA methylation states but uniform transcriptome•Neurog3+ cells have distinct transcriptome, DNA methylation state, and cell fate•β-biasing Neurog3+ progenitors co-express Myt1 and have higher Arx enhancer methylation•Increased methylation in Arx promoter drives progenitors to the β cell lineage During embryogenesis, seemingly equivalent progenitors produce distinct cell types. The mechanisms driving this divergence are unknown. Liu et al. show that the pancreatic progenitors before endocrine determination are transcriptionally uniform but epigenetically distinct pools with different DNA methylation in gene enhancers. This epigenetic variation biases progenitors toward specific islet-cell fate.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2018.11.048