TRIM28 Is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming

Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their geno...

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Veröffentlicht in:Stem cells (Dayton, Ohio) Jg. 35; H. 1; S. 147 - 157
Hauptverfasser: Miles, Denise Catherine, de Vries, Nienke Alexandra, Gisler, Santiago, Lieftink, Cor, Akhtar, Waseem, Gogola, Ewa, Pawlitzky, Inka, Hulsman, Danielle, Tanger, Ellen, Koppens, Martijn, Beijersbergen, Roderick Leonardus, van Lohuizen, Maarten
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Oxford University Press 01.01.2017
Schlagworte:
Animals
Cell Proliferation
Cellular Reprogramming - genetics
Chromatin
Chromatin - metabolism
Domains
Endogenous retroviruses
Endogenous Retroviruses - metabolism
Epigenesis, Genetic
Epigenetics
Gene expression
Gene Knockdown Techniques
Genomes
Histone-Lysine N-Methyltransferase
Histones - metabolism
Induced pluripotent stem cells
Lysine - metabolism
Methylation
Mice, Transgenic
Models, Biological
Pluripotency
Pluripotent Stem Cells - cytology
Pluripotent Stem Cells - metabolism
Reprogramming
Retroviridae
RNA, Small Interfering - metabolism
Somatic cells
Stem cells
Trim28
Tripartite Motif-Containing Protein 28 - metabolism
Up-Regulation - genetics
Epigenetics
Reprogramming
Induced pluripotent stem cells
Trim28
ISSN:1066-5099, 1549-4918, 1549-4918
Online-Zugang:Volltext
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Zusammenfassung:Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large‐scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming. We have uncovered an important role for TRIM28 in cells resisting transition between somatic and pluripotent states. TRIM28 achieves this by maintaining the H3K9me3 repressed state and keeping endogenous retroviruses (ERVs) silenced. We propose that knockdown of TRIM28 during reprogramming results in more plastic H3K9me3 domains, dysregulation of genes nearby H3K9me3 marks, and up regulation of ERVs, thus facilitating the transition through reprogramming. Stem Cells 2017;35:147–157 Model of TRIM28 function during reprogramming A) Ectopic expression of Oct4, Sox2, Klf4 and c‐Myc (OSKM) induces the reprogramming of somatic cells into induced pluripotent stem cells at a low efficiency B) Ectopic expression of OSKM along with knock down of TRIM28 increases the expression of genes nearby H3K9me3, and induces the expression of endogenous retroviruses. This decondensed chromatin state increases the reprogramming efficiency.
Bibliographie:This article was published online on 06 July 2016. An error was subsequently identified in the coding of the author line and running head. This notice is included in the online and print versions to indicate that both have been corrected 25 July 2016.
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ISSN:1066-5099
1549-4918
1549-4918
DOI:10.1002/stem.2453