Figure 7.

PTF1A^enhP creates an active enhancer cluster in mouse and human MPCs

(A) Regulatory landscape of the human PTF1A locus in PTF1A^+/+ and PTF1A^enhΔ/enhΔ MPCs. Six H3K27ac-enriched putative enhancers and the PTF1A promoter, most of which show strong mediator (MED1) binding, are shaded in gray. All show absent activity in PTF1A^enhΔ/enhΔ MPCs (q < 0.05). ChIP-seq tracks show a MACS2 −log₁₀ p values.

(B) scATAC-seq profiles for MPCs from Ptf1a^+/+ and Ptf1a^enhΔ/enhΔ E10.5 pancreatic buds showed chromatin accessibility at Ptf1a and E1-E6 regions orthologous to human enhancers, highlighted in gray. All showed loss in Ptf1a^enhΔ/enhΔ cells (q < 0.1, log₂FC < −0.5). Conservation tracks show multiple alignments between 100 vertebrate species.

(C and D) H3K27ac at the PTF1A locus in 2 hPSC-derived pancreatic progenitor datasets (Alvarez-Dominguez et al., 2020; Geusz et al., 2021). Both used a protocol that generates two stages of early pancreatic progenitors: PP1 PDX1+ cells that do not express MPC markers such as NKX6-1, PP2 PDX1+, and NKX6.1+ cells that are comparable with stage 4 MPCs from the current study. In both datasets, H3K27ac enrichment at PTF1A^enhP preceded that of all other enhancers.

(E) Summary model illustrating how PTF1A^enhP precedes and activates the enhancer cluster in the PTF1A locus. See also Figure S7.