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Endocrine islet beta-cell subtypes with differential function are derived from biochemically distinct embryonic endocrine islet progenitors that are regulated by maternal nutrients

ABSTRACT: Endocrine islet beta cells comprise heterogenous cell subsets. Yet the origin, stability, and physiological significance of these subsets remain largely unknown. Using combinatorial cell lineage tracing, scRNA-seq, and DNA methylation analysis, we show here that embryonic islet progenitors with differential gene expression and DNA methylation produce stable beta-cell subtypes of different function and viability in adult mice. Differentially expressed genes, including the Myt transcription factors, voltage-gated channels, and Ca2+-sensor synaptotagmins, contribute to the functional differences of these subtypes. Maternal overnutrition, a major diabetes risk factor, reduces the proportion of endocrine progenitors of the better-functionality beta-cell subtype. Intriguingly, the gene signature that defines mouse beta-cell subtypes can reliably divide human cells into two populations, with the proportion of better-functionality beta cells reduced in diabetic donors. These results establish that some beta-cell subtypes are determined via DNA methylation in embryonic islet progenitors, which is regulated by diabetes-causing maternal factors. The implication is that modulating DNA methylation in islet progenitors can be explored to improve beta-cell function in the prevention and therapy of diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE254955 | GEO | 2025/02/01

REPOSITORIES: GEO

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	GSE254955_RAW.tar	Raw
	GSE254955_p2_DMR_b1_lt_b2.dmr.txt.gz	Txt
	GSE254955_p2_DMR_b1_lt_b2_at_least_50bp_and_2_CpGsites_significantly_diff_methylated.txt.gz	Txt
	GSE254955_p2_DMR_b2_lt_b1.dmr.txt.gz	Txt

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