ESET methylates UBF at K232/254 and regulates nucleolar heterochromatin plasticity and rDNA transcription.
The remodeling of chromatin in the nucleolus is important for the control of ribosomal DNA (rDNA) transcription and ribosome biogenesis. Herein, we found that upstream binding factor (UBF) interacts with ESET, a histone H3K9 methyltransferase and is trimethylated at Lys (K) 232/254 by ESET. UBF trimethylation leads to nucleolar chromatin condensation and decreased rDNA transcriptional activity. UBF mutations at K232/254A and K232/254R restored rDNA transcriptional activity in response to ESET. Both ESET-ΔSET mutant and knockdown of ESET by short hairpin RNA reduced trimethylation of UBF and resulted in the restoration of rDNA transcription. Atomic force microscopy confirmed that UBF trimethylated by ESET modulates the plasticity of nucleolar chromatin. We further demonstrated that UBF trimethylation at K232/254 by ESET deregulates rDNA transcription in a cell model of Huntington's disease. Together, our findings show that a novel epigenetic modification of UBF is linked to impaired rDNA transcription and nucleolar chromatin remodeling, which may play key roles in the pathogenesis of neurodegeneration.
Department of Biomedical Sciences, World Class University Neurocytomics Group, Seoul National University College of Medicine, Seoul 110-799, South Korea, Medical Engineering, Seoul National University College of Medicine, Seoul 110-799, South Korea, Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea, VA Boston Healthcare System, Boston, MA 02130, USA, Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA, Department of Orthopedics and Division of Hematology, University of Washington School of Medicine, Seattle, WA 98195, USA and Medical Research Service, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
Yu Jin
YJ
Hwang
Dohyun
D
Han
Ki Yoon
KY
Kim
Sun-Joon
SJ
Min
Neil W
NW
Kowall
Liu
L
Yang
Junghee
J
Lee
Youngsoo
Y
Kim
Hoon
H
Ryu
D000818:Animals; D002460:Cell Line; D002466:Cell Nucleolus / Q000201:enzymology* / Q000235:genetics*; D004275:DNA, Ribosomal / Q000378:metabolism*; D006570:Heterochromatin / Q000737:chemistry*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology; D008745:Methylation; D051379:Mice; D009154:Mutation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D004275:DNA, Ribosomal; D006570:Heterochromatin; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D011495:Histone-Lysine N-Methyltransferase