Combined modulation of polycomb and trithorax genes rejuvenates β cell replication
Josie X. Zhou, Sangeeta Dhawan, Hualin Fu, Emily Snyder, Rita Bottino, Sharmistha Kundu, Seung K. Kim, Anil Bhushan
Josie X. Zhou, Sangeeta Dhawan, Hualin Fu, Emily Snyder, Rita Bottino, Sharmistha Kundu, Seung K. Kim, Anil Bhushan
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Research Article Metabolism

Combined modulation of polycomb and trithorax genes rejuvenates β cell replication

Abstract

Inadequate functional β cell mass underlies both type 1 and type 2 diabetes. β Cell growth and regeneration also decrease with age through mechanisms that are not fully understood. Age-dependent loss of enhancer of zeste homolog 2 (EZH2) prevents adult β cell replication through derepression of the gene encoding cyclin-dependent kinase inhibitor 2a (INK4a). We investigated whether replenishing EZH2 could reverse the age-dependent increase of Ink4a transcription. We generated an inducible pancreatic β cell–specific Ezh2 transgenic mouse model and showed that transgene expression of Ezh2 was sufficient to increase β cell replication and regeneration in young adult mice. In mice older than 8 months, induction of Ezh2 was unable to repress Ink4a. Older mice had an enrichment of a trithorax group (TrxG) protein complex at the Ink4a locus. Knockdown of TrxG complex components, in conjunction with expression of Ezh2, resulted in Ink4a repression and increased replication of β cells in aged mice. These results indicate that combined modulation of polycomb group proteins, such as EZH2, along with TrxG proteins to repress Ink4a can rejuvenate the replication capacity of aged β cells. This study provides potential therapeutic targets for expansion of adult β cell mass.

Authors

Josie X. Zhou, Sangeeta Dhawan, Hualin Fu, Emily Snyder, Rita Bottino, Sharmistha Kundu, Seung K. Kim, Anil Bhushan

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Figure 5

Knockdown of JmjD3 facilitates EZH2 recruitment to the Ink4a locus and increased β cell replication.

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Knockdown of JmjD3 facilitates EZH2 recruitment to the Ink4a locus and i...
(A) JMJD3 mRNA levels in juvenile (<10 years) and adult (≥10 years) human islets, as show by quantitative RT-PCR. (B) ChIP analysis showing JmjD3 binding to the Ink4a locus in human islets. (C) 8-month-old bEzTG islets were treated with scrambled siRNA (100 pM), Dox (1 μg/ml), JMJD3 siRNA (100 pM), and both Dox and JMJD3 siRNA for 48 hours. Islet sections were immunostained for Ki67 (red) and Pdx1 (green) (original magnification, ×20). (D) Percentage of Ki67-positive endocrine cells in each experiment group (5 pancreatic sections per animal). *P < 0.05. (E–J) Representative ChIP results for the indicated antibodies at the Ink4a locus in islets treated with the same experiment conditions as in E. n = 3 experiments.