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@article{Yu:2024:10.1007/s00125-024-06123-6,
author = {Yu, V and Yong, F and Marta, A and Khadayate, S and Osakwe, A and Bhattacharya, S and Varghese, S and Chabosseau, P and Tabibi, S and Chen, K and Georgiadou, E and Parveen, N and Suleiman, M and Stamoulis, Z and Marselli, L and De, Luca C and Tesi, M and Ostinelli, G and Delgadillo-Silva, L and Wu, X and Hatanaka, Y and Montoya, A and Elliott, J and Bhavik, P and Demchenko, N and Whilding, C and Hajkova, P and Shliaha, P and Kramer, H and Ali, Y and Marchetti, P and Sladek, R and Dhawan, S and Withers, D and Rutter, G and Millership, S},
doi = {10.1007/s00125-024-06123-6},
journal = {Diabetologia},
title = {Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity},
url = {http://dx.doi.org/10.1007/s00125-024-06123-6},
year = {2024}
}

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TY  - JOUR
AB  - Aims/hypothesis: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly-connected ‘hub’ cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility which we explore here by focussing on the imprinted gene neuronatin (Nnat), which is required for normal insulin synthesis and secretion.Methods: Single cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing eGFP under the control of the Nnat enhancer/promoter regions were generated for fluorescence-activated cell (FAC) sorting of beta cells and downstream analysis of CpG methylation by bisulphite and RNA sequencing, respectively. Animals deleted for the de novo methyltransferase, DNMT3A from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 and Cal-590. Insulin secretion was measured using Homogeneous Time Resolved Fluorescence Imaging.Results: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic data sets demonstrated the early establishment of Nnat-positive and negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed
AU  - Yu,V
AU  - Yong,F
AU  - Marta,A
AU  - Khadayate,S
AU  - Osakwe,A
AU  - Bhattacharya,S
AU  - Varghese,S
AU  - Chabosseau,P
AU  - Tabibi,S
AU  - Chen,K
AU  - Georgiadou,E
AU  - Parveen,N
AU  - Suleiman,M
AU  - Stamoulis,Z
AU  - Marselli,L
AU  - De,Luca C
AU  - Tesi,M
AU  - Ostinelli,G
AU  - Delgadillo-Silva,L
AU  - Wu,X
AU  - Hatanaka,Y
AU  - Montoya,A
AU  - Elliott,J
AU  - Bhavik,P
AU  - Demchenko,N
AU  - Whilding,C
AU  - Hajkova,P
AU  - Shliaha,P
AU  - Kramer,H
AU  - Ali,Y
AU  - Marchetti,P
AU  - Sladek,R
AU  - Dhawan,S
AU  - Withers,D
AU  - Rutter,G
AU  - Millership,S
DO  - 10.1007/s00125-024-06123-6
PY  - 2024///
SN  - 0012-186X
TI  - Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity
T2  - Diabetologia
UR  - http://dx.doi.org/10.1007/s00125-024-06123-6
UR  - https://link.springer.com/article/10.1007/s00125-024-06123-6
UR  - http://hdl.handle.net/10044/1/109256
ER  -

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