Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation.
The molecular mechanisms that regulate the age-induced increase of p16(INK4a) expression associated with decreased beta-cell proliferation and regeneration are not well understood. We report that in aged islets, derepression of the Ink4a/Arf locus is associated with decreased Bmi-1 binding, loss of H2A ubiquitylation, increased MLL1 recruitment, and a concomitant increase in H3K4 trimethylation. During beta-cell regeneration these histone modifications are reversed resulting in reduced p16(INK4a) expression and increased proliferation. We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control beta-cell proliferation during aging and regeneration.
Dhawan
Sangeeta
S
Larry L. Hillblom Islet Research Center, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90024, USA.
Tschen
Shuen-Ing
SI
Bhushan
Anil
A
D000375:Aging; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1