PMID- 30452683
OWN - NLM
STAT- MEDLINE
DCOM- 20190516
LR  - 20201209
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 27
IP  - 23
DP  - 2018 Dec 1
TI  - Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its 
      demise by polyQ-expanded huntingtin mutations.
PG  - 4117-4134
LID - 10.1093/hmg/ddy304 [doi]
AB  - Pluripotent stem cells are invaluable resources to study development and disease, 
      holding a great promise for regenerative medicine. Here we use human embryonic 
      stem cells (hESCs) and induced pluripotent stem cells (iPSCs) from patients with 
      Huntington's disease (HD-iPSCs) to shed light into the normal function of 
      huntingtin (HTT) and its demise in disease. We find that HTT binds ATF7IP, a 
      regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the 
      interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators 
      and transcriptional repressors, maintaining low levels of H3K9 trimethylation 
      (H3K9me3) in hESCs. Loss of HTT promotes global increased H3K9me3 levels and 
      enrichment of H3K9me3 marks at distinct genes, including transcriptional 
      regulators of neuronal differentiation. Although these genes are normally 
      expressed at low amounts in hESCs, HTT knockdown (KD) reduces their induction 
      during neural differentiation. Notably, mutant expanded polyglutamine repeats in 
      HTT diminish its interaction with ATF7IP-SETDB1 complex and trigger H3K9me3 in 
      HD-iPSCs. Conversely, KD of ATF7IP in HD-iPSCs reduces H3K9me3 alterations and 
      ameliorates gene expression changes in their neural counterparts. Taken together, 
      our results indicate ATF7IP as a potential target to correct aberrant H3K9me3 
      levels induced by mutant HTT.
FAU - Irmak, Dilber
AU  - Irmak D
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Fatima, Azra
AU  - Fatima A
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Gutierrez-Garcia, Ricardo
AU  - Gutierrez-Garcia R
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Rinschen, Markus M
AU  - Rinschen MM
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Wagle, Prerana
AU  - Wagle P
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Altmuller, Janine
AU  - Altmuller J
AD  - Center for Molecular Medicine Cologne (CMMC), University of Cologne, 
      Robert-Koch-Strasse 21, Cologne, Germany.
AD  - Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
FAU - Arrigoni, Laura
AU  - Arrigoni L
AD  - Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
FAU - Hummel, Barbara
AU  - Hummel B
AD  - Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
FAU - Klein, Corinna
AU  - Klein C
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Frese, Christian K
AU  - Frese CK
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
FAU - Sawarkar, Ritwick
AU  - Sawarkar R
AD  - Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
FAU - Rada-Iglesias, Alvaro
AU  - Rada-Iglesias A
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
AD  - Center for Molecular Medicine Cologne (CMMC), University of Cologne, 
      Robert-Koch-Strasse 21, Cologne, Germany.
FAU - Vilchez, David
AU  - Vilchez D
AD  - Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (ATF7IP protein, human)
RN  - 0 (HTT protein, human)
RN  - 0 (Heterochromatin)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Peptides)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - 26700-71-0 (polyglutamine)
RN  - EC 2.1.1.- (Histone Methyltransferases)
RN  - EC 2.1.1.- (Protein Methyltransferases)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.1.1.43 (SETDB1 protein, human)
SB  - IM
MH  - Cell Differentiation/genetics
MH  - Embryonic Stem Cells/metabolism/pathology
MH  - Gene Expression Regulation, Developmental
MH  - Gene Knockdown Techniques
MH  - Heterochromatin/genetics
MH  - Histone Methyltransferases/genetics
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Huntingtin Protein/*genetics
MH  - Huntington Disease/*genetics/pathology
MH  - Induced Pluripotent Stem Cells/metabolism/pathology
MH  - Lentivirus/genetics
MH  - Neurons/metabolism/pathology
MH  - Peptides/genetics
MH  - Protein Methyltransferases/*genetics
MH  - Repressor Proteins
MH  - Transcription Factors/*genetics
EDAT- 2018/11/20 06:00
MHDA- 2019/05/17 06:00
CRDT- 2018/11/20 06:00
PHST- 2018/05/09 00:00 [received]
PHST- 2018/08/10 00:00 [accepted]
PHST- 2018/11/20 06:00 [entrez]
PHST- 2018/11/20 06:00 [pubmed]
PHST- 2019/05/17 06:00 [medline]
AID - 5078637 [pii]
AID - 10.1093/hmg/ddy304 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2018 Dec 1;27(23):4117-4134. doi: 10.1093/hmg/ddy304.