Oct4-Mediated Inhibition of Lsd1 Activity Promotes the Active and Primed State of Pluripotency Enhancers

Autor: Debapriya Saha, Humaira Gowher, Sagar M. Utturkar, James A. Breedlove, Stephen McCune, Nadia A. Lanman, Putu Ayu Sudyanti, Ming He, Lama AlAbdi, Brice H. Spears, Mohd Saleem Dar
Rok vydání: 2020
Předmět:
Male
Pluripotent Stem Cells
0301 basic medicine
animal structures
Models
Biological
Article
General Biochemistry
Genetics and Molecular Biology
Epigenesis
Genetic
Histones
03 medical and health sciences
0302 clinical medicine
Histone demethylation
Cancer stem cell
Carcinoma
Embryonal
Cell Line
Tumor
Gene silencing
Humans
Enhancer
lcsh:QH301-705.5
Psychological repression
030304 developmental biology
Demethylation
Histone Demethylases
0303 health sciences
Chemistry
Cell Differentiation
DNA Methylation
Embryonic stem cell
In vitro
Chromatin
Cell biology
Enhancer Elements
Genetic
030104 developmental biology
lcsh:Biology (General)
030220 oncology & carcinogenesis
embryonic structures
DNA methylation
Biocatalysis
sense organs
Stem cell
Octamer Transcription Factor-3
030217 neurology & neurosurgery
Zdroj: Cell Reports, Vol 30, Iss 5, Pp 1478-1490.e6 (2020)
Cell Rep
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2019.11.040
Popis: Summary: An aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance the tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1-mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4-overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a “primed” enhancer state that is susceptible to reactivation, leading to aberrant PpG expression. : AlAbdi et al. show that aberrant expression of Oct4 in cancer stem cells can facilitate the establishment of the “primed” enhancer state of pluripotency genes. Reactivation of these enhancers would support tumorigenicity. Keywords: pluripotency, enhancers, Dnmt3a, DNA methylation, embryonal carcinoma cells, Lsd1, histone demethylation, Oct4, cancer stem cells, enhancer priming
Databáze: OpenAIRE
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