RT Journal Article
SR Electronic
T1 The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 205641
DO 10.1101/205641
A1 Tess Tsai-Hsiu Lu
A1 Steffen Heyne
A1 Erez Dror
A1 Eduard Casas
A1 Laura Leonhardt
A1 Thorina Boenke
A1 Chih-Hsiang Yang
A1 Sagar
A1 Laura Arrigoni
A1 Kevin Dalgaard
A1 Raffaele Teperino
A1 Lennart Enders
A1 Madhan Selvaraj
A1 Marius Ruf
A1 Sunil Jayaramaiah Raja
A1 Huafeng Xie
A1 Ulrike Boenisch
A1 Stuart H. Orkin
A1 Francis C Lynn
A1 Brad G. Hoffman
A1 Dominic Grün
A1 Tanya Vavouri
A1 Adelheid Lempradl
A1 J. Andrew Pospisilik
YR 2017
UL http://biorxiv.org/content/early/2017/10/20/205641.abstract
AB Chromatin is the physical template that stabilizes and specifies transcriptional programs. To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combined deep epigenome mapping with single cell transcriptomics to mine for evidence of chromatin dysregulation in type-2 diabetes. We identify two chromatin-state signatures that track the trajectory of β-cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-domains and a loss of expression at a subclass of highly active domains containing key lineage-defining genes. β-cell specific deletion of Polycomb (Eed/PRC2) triggers parallel transcriptional signatures. Intriguingly, these β-cell Eed-knockouts also exhibit highly penetrant hyperglycemia-independent dedifferentiation indicating that Polycomb dysregulation sensitizes the β-cell for dedifferentiation. These findings provide novel resources for exploring transcriptional and epigenetic control of β-cell (dys)function. They identify PRC2 as necessary for long-term maintenance of β-cell identity. The data suggest a two-hit model for loss of β-cell identity in diabetes and highlight epigenetic therapeutic potential to block dedifferentiation.