β-Cell-Specific E2f1 Deficiency Impairs Glucose Homeostasis, β-Cell Identity, and Insulin Secretion

被引：4

作者：

Oger, Frederik ^{[1
]}

Bourouh, Cyril ^{[1
]}

Friano, Marika Elsa ^{[2
]}

Courty, Emilie ^{[3
]}

Rolland, Laure ^{[3
]}

Gromada, Xavier ^{[1
]}

Moreno, Maeva ^{[1
]}

Carney, Charlene ^{[1
]}

Rabhi, Nabil ^{[4
]}

Durand, Emmanuelle ^{[1
]}

Amanzougarene, Souhila ^{[1
]}

Berberian, Lionel ^{[1
]}

Derhourhi, Mehdi ^{[1
]}

Blanc, Etienne ^{[1
]}

Hannou, Sarah Anissa ^{[1
]}

Denechaud, Pierre-Damien ^{[5
]}

Benfodda, Zohra ^{[6
]}

Meffre, Patrick ^{[6
]}

Fajas, Lluis ^{[5
]}

Kerr-Conte, Julie ^{[7
]}

Pattou, Francois ^{[7
]}

Froguel, Philippe ^{[1
,8
]}

Pourcet, Benoit ^{[9
]}

Bonnefond, Amelie ^{[1
,8
]}

Collombat, Patrick ^{[2
]}

Annicotte, Jean-Sebastien ^{[3
]}

机构：

[1] Univ Lille, CHU Lille, Inst Pasteur Lille, INSERM,U1283 UMR8199,European Genom Inst Diabet EG, Lille, France

[2] Univ Cote Azur, Inst Biol Valrose, INSERM, CNRS, Nice, France

[3] Univ Lille, Inst Pasteur Lille, INSERM, U1167 RID AGE Facteurs Risque & Determinants Mol M, Lille, France

[4] Boston Univ, Sch Med, Dept Biochem, Boston, MA USA

[5] Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland

[6] Univ Nimes, UPR CHROME, Nimes, France

[7] Univ Lille, Inst Pasteur Lille, INSERM, U1190 EGID, Lille, France

[8] Imperial Coll London, Hammersmith Hosp, Dept Metab, London, England

[9] Univ Lille, Inst Pasteur Lille, INSERM, U1011 EGID, Lille, France

来源：

DIABETES | 2023年 / 72卷 / 08期

关键词：

BETA-CELL IDENTITY; PANCREAS DEVELOPMENT; ECTOPIC EXPRESSION; CHROMATIN-STATE; CYCLE CONTROL; ALPHA; TRANSCRIPTOME; PROLIFERATION; PROGRESSION; ISLETS;

D O I：

10.2337/db22-0604

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The loss of pancreatic & beta;-cell identity has emerged as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell-cycle regulator and transcription factor E2F1 in the maintenance of & beta;-cell identity, insulin secretion, and glucose homeostasis. We show that the & beta;-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, altered endocrine cell mass, downregulation of many & beta;-cell genes, and concomitant increase of non-& beta;-cell markers. Mechanistically, epigenomic profiling of the promoters of these non-& beta;-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic, and epigenomic signatures are associated with these & beta;-cell dysfunctions, with E2F1 directly regulating several & beta;-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of & beta;-cell identity genes. Our data suggest that E2F1 is critical for maintaining & beta;-cell identity and function through sustained control of & beta;-cell and non-& beta;-cell transcriptional programs.

引用

页码：1112 / 1126

页数：15

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