Abstract：
:Proliferation of pancreatic islet beta cells is an important mechanism for self-renewal and for adaptive islet expansion. Increased expression of the Ink4a/Arf locus, which encodes the cyclin-dependent kinase inhibitor p16(INK4a) and tumor suppressor p19(Arf), limits beta-cell regeneration in aging mice, but the basis of beta-cell Ink4a/Arf regulation is poorly understood. Here we show that Enhancer of zeste homolog 2 (Ezh2), a histone methyltransferase and component of a Polycomb group (PcG) protein complex, represses Ink4a/Arf in islet beta cells. Ezh2 levels decline in aging islet beta cells, and this attrition coincides with reduced histone H3 trimethylation at Ink4a/Arf, and increased levels of p16(INK4a) and p19(Arf). Conditional deletion of beta-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Ink4a/Arf locus, leading to precocious increases of p16(INK4a) and p19(Arf). These mutant mice had reduced beta-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes rescued by germline deletion of Ink4a/Arf. beta-Cell destruction with streptozotocin in controls led to increased Ezh2 expression that accompanied adaptive beta-cell proliferation and re-establishment of beta-cell mass; in contrast, mutant mice treated similarly failed to regenerate beta cells, resulting in lethal diabetes. Our discovery of Ezh2-dependent beta-cell proliferation revealed unique epigenetic mechanisms underlying normal beta-cell expansion and beta-cell regenerative failure in diabetes pathogenesis.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Chen H,Gu X,Su IH,Bottino R,Contreras JL,Tarakhovsky A,Kim SKdoi
10.1101/gad.1742509subject
Has Abstractpub_date
2009-04-15 00:00:00pages
975-85issue
8eissn
0890-9369issn
1549-5477pii
23/8/975journal_volume
23pub_type
杂志文章abstract：:We have analyzed pre-mRNA splicing in yeast extracts immunodepleted of the PRP18 protein. We find that while the first step of splicing (cleavage at the 5' splice site, and generation of the exon 1 and lariat intermediates) is unaffected by the absence of PRP18, the second step of splicing (excision of the lariat intr...
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