Irmak, Dilber, Fatima, Azra, Gutierrez-Garcia, Ricardo, Rinschen, Markus M., Wagle, Prerana, Altmueller, Janine, Arrigoni, Laura, Hummel, Barbara ORCID: 0000-0001-6563-3675, Klein, Corinna, Frese, Christian K., Sawarkar, Ritwick, Rada-Iglesias, Alvaro ORCID: 0000-0001-7137-1341 and Vilchez, David ORCID: 0000-0002-0801-0743 (2018). Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations. Hum. Mol. Genet., 27 (23). S. 4117 - 4135. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Irmak, DilberUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatima, AzraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutierrez-Garcia, RicardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagle, PreranaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arrigoni, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hummel, BarbaraUNSPECIFIEDorcid.org/0000-0001-6563-3675UNSPECIFIED
Klein, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frese, Christian K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sawarkar, RitwickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rada-Iglesias, AlvaroUNSPECIFIEDorcid.org/0000-0001-7137-1341UNSPECIFIED
Vilchez, DavidUNSPECIFIEDorcid.org/0000-0002-0801-0743UNSPECIFIED
URN: urn:nbn:de:hbz:38-163843
DOI: 10.1093/hmg/ddy304
Journal or Publication Title: Hum. Mol. Genet.
Volume: 27
Number: 23
Page Range: S. 4117 - 4135
Date: 2018
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
WILD-TYPE; MUTANT HUNTINGTIN; NEURAL DIFFERENTIATION; TARGETED DISRUPTION; MOUSE MODEL; TRANSCRIPTIONAL REPRESSION; HETEROCHROMATIN FORMATION; EPIGENETIC DYSREGULATION; POLYGLUTAMINE EXPANSION; EMBRYONIC LETHALITYMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16384

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