Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells.
Long interspersed element-1 (LINE-1 or L1) retrotransposition continues to affect human genome evolution. L1s can retrotranspose in the germline, during early development and in select somatic cells; however, the host response to L1 retrotransposition remains largely unexplored. Here we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors rapidly reverses this silencing, and chromatin immunoprecipitation experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing was also observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukaemia virus or human immunodeficiency virus, suggesting that these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, in itself, is not sufficient to reactivate previously silenced reporter genes. Thus, our data indicate that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition.
Garcia-Perez
Jose L
JL
Department of Human Genetics, 1241 East Catherine Street, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA. josel.garcia.perez@juntadeandalucia.es
Morell
Maria
M
Scheys
Joshua O
JO
Kulpa
Deanna A
DA
Morell
Santiago
S
Carter
Christoph C
CC
Hammer
Gary D
GD
Collins
Kathleen L
KL
O'Shea
K Sue
KS
Menendez
Pablo
P
Moran
John V
JV
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006678:HIV / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008979:Moloney murine leukemia virus / Q000235:genetics; D018626:Retroelements / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D018626:Retroelements