Lsh participates in DNA methylation and silencing of stem cell genes.
Transcriptional control of stem cell genes is a critical step in differentiation of embryonic stem cells and in reprogramming of somatic cells into stem cells. Here we report that Lsh, a regulator of repressive chromatin at retrotransposons, also plays an important role in silencing of stem cell-specific genes such as Oct4. We found that CpG methylation is gained during in vitro differentiation of several stem cell-specific genes (in 11 of 12 promoter regions) and thus appears to be a common epigenetic mark. Lsh depletion prevents complete silencing of stem cell gene expression and moreover promotes the maintenance of stem cell characteristics in culture. Lsh is required for establishment of DNA methylation patterns at stem cell genes during differentiation, in part by regulating access of Dnmt3b to its genomic targets. Our results indicate that Lsh is involved in the control of stem cell genes and suggest that Lsh is an important epigenetic modulator during early stem cell differentiation.
Xi
Sichuan
S
Laboratory of Cancer Prevention, SAIC-Frederick, National Cancer Institute, Frederick, MD 21701, USA.
Geiman
Theresa M
TM
Briones
Victorino
V
Guang Tao
Yong
Y
Xu
Hong
H
Muegge
Kathrin
K
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004815:Epidermal Growth Factor / Q000235:genetics; D020868:Gene Silencing; D055451:Growth Differentiation Factor 3 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000235:genetics; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D002868:Chromosomal Proteins, Non-Histone; D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D004815:Epidermal Growth Factor; D055451:Growth Differentiation Factor 3; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C462180:Dppa3 protein, mouse; C525975:Gdf3 protein, mouse; C475540:Nanog protein, mouse; C494174:Pou5f1 protein, mouse; C489450:Tdgf1 protein, mouse; C491758:lymphoid specific helicase, mouse