Dynamics of chromatin marks and the role of JMJD3 during pancreatic endocrine cell fate commitment

Abstract

Pancreatic endocrine lineages are derived from pancreatic progenitors that undergo a cell fate transition requiring a switch from low to high Ngn3 expression. However, the underlying chromatin regulatory mechanisms are unclear. Here, we performed epigenomic analysis of gene regulatory loci featuring histone marks in cells with low or high level of Ngn3 expression. In combination with transcriptomic analysis, we discovered that in Ngn3-high cells, the removal of H3K27me3 was associated with the activation of key transcription factors and the establishment of primed and active enhancers. Deletion of , a histone demethylase for H3K27me3, at the pancreatic progenitor stage impaired the efficiency of endocrine cell fate transition and thereafter islet formation. Curiously, single-cell RNA-seq revealed that the transcriptome and developmental pathway of Ngn3-high cells were not affected by the deletion of Our study indicates sequential chromatin events and identifies a crucial role for Jmjd3 in regulating the efficiency of the transition from Ngn3-low to Ngn3-high cells.

Defining multistep cell fate decision pathways during pancreatic development at single‐cell resolution

“…Point size reflects transcript length. EThe t‐SNE plots showed no obvious batch effects of replicated experiments. * indicates cells from our recently published work (Li et al , ; Yu et al , ). Ft‐SNE analysis identified nonpancreatic and pancreatic epithelial lineage cells. The color code, marker gene, and cell count for each cell type are provided next to the t‐SNE plot. GExpression patterns of marker genes in (F). HThe overview of cell type distribution in certain mouse strains at various time points.…”

“…The numbers separated by slashes represent the number of cells produced in each experiment. § represents the cells from Pdx1‐GFP highly expressing cells, *represents the single‐cell datasets from published resources (GEO: GSE86225; Li et al , ), **represents the single‐cell datasets from published resources (GEO: GSE84324; Yu et al , ), and ***represents the single‐cell datasets from published resources (GEO: GSE89798; Sznurkowska et al , ). FACS gating strategies for purifying pancreatic cells at multiple developmental stages from various mouse strains. The pancreatic tissues from WT embryos were used as negative controls (upper panel).…”

Comprehensive single cell mRNA profiling reveals a detailed roadmap for pancreatic endocrinogenesis

“…Yet, during progressive lineage restriction from specified EP progenitors to determined EP precursors the molecular signature changes over time and the mechanisms underpinning lineage allocation towards a specific endocrine subtype fate have remained largely elusive. Although several recent studies (Byrnes et al, 2018;Krentz et al, 2018;Ramond et al, 2018;Scavuzzo et al, 2018;Sharon et al, 2019;Stanescu et al, 2016;Yu et al, 2018Yu et al, , 2019 have shed light on the transcriptional profiles of EPs, the importance of these cells for endocrine cell formation still necessitates a comprehensive temporally resolved and fine-grained mapping of gene expression on the single cell level. The low percentage of EPs within the embryonic pancreas together with the limitation of transgenic reporter lines to reflect accurately the transient expression of the Ngn3 protein have been major obstacles to establishing a detailed roadmap of endocrinogenesis.…”

Epigenetic Control of Pancreatic Regeneration in Diabetes

“…Neurogenin 3 is a basic helix-loop-helix-containing transcription factor whose targeted disruption leads to a lack of pancreatic endocrine cells in mice [ 18 ]. Yu et al confirmed that, in the pancreatic context, the levels of Ngn3 directed cell fate [ 25 ]. A low level was associated with the maintenance of the pluripotent state, whereas a high level of Ngn3 expression was found to induce endocrine cell lineage allocation, Figure 1 .…”

“…Recent work by Yu et al allowed us to gain further insight into the Ngn3-induced transition of endocrine progenitor cells to endocrine-committed cells [ 25 ]. Neurogenin 3 is a basic helix-loop-helix-containing transcription factor whose targeted disruption leads to a lack of pancreatic endocrine cells in mice [ 18 ].…”