Comprehensive dynamic chromatin maps reveal core regulatory circuits of human pancreatic differentiation

Juan R. Alvarez-Dominguez1, Julie Donaghey1, Niloofar Rasouli1, Jennifer H. R. Kenty1, Aharon Helman1, Jocelyn Charlton1,2, Juerg R. Straubhaar1, Alexander Meissner1,2, Douglas A. Melton1

Investigating human stem cell differentiation into pancreatic islets in vitro offers an unparalleled chance to dissect mechanisms that operate during human fetal development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from stem cells to mature islet cells. These dynamics reveal that enhancer repertoires are largely reset upon lineage branching. We find that endocrine commitment is foreshadowed by widespread yet highly dynamic enhancer priming, and show that priming of α-cell-specific enhancers steers polyhormonal cells toward an α-cell fate. We dissect pioneer factors and core regulatory circuits across islet differentiation and maturation stages, uncovering LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural β-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation.

1 Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
2 Department of Genome Regulation, Max Planck Institute for Molecular Genetics Berlin, 14195 Germany

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Chromosome Start End Enhancer ID closesst_NM_TS