An Sp1/Sp3 binding polymorphism confers methylation protection.

PLoS Genetics
Yanis A BoumberJ P Issa

Abstract

Hundreds of genes show aberrant DNA hypermethylation in cancer, yet little is known about the causes of this hypermethylation. We identified RIL as a frequent methylation target in cancer. In search for factors that influence RIL hypermethylation, we found a 12-bp polymorphic sequence around its transcription start site that creates a long allele. Pyrosequencing of homozygous tumors revealed a 2.1-fold higher methylation for the short alleles (P<0.001). Bisulfite sequencing of cancers heterozygous for RIL showed that the short alleles are 3.1-fold more methylated than the long (P<0.001). The comparison of expression levels between unmethylated long and short EBV-transformed cell lines showed no difference in expression in vivo. Electrophorectic mobility shift assay showed that the inserted region of the long allele binds Sp1 and Sp3 transcription factors, a binding that is absent in the short allele. Transient transfection of RIL allele-specific transgenes showed no effects of the additional Sp1 site on transcription early on. However, stable transfection of methylation-seeded constructs showed gradually decreasing transcription levels from the short allele with eventual spreading of de novo methylation. In contrast, the long a...Continue Reading

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Citations

Jan 3, 2014·The Journal of Clinical Investigation·Jean-Pierre Issa
Apr 24, 2014·Proceedings of the National Academy of Sciences of the United States of America·Xiang LiTimothy W Bredy
Jun 12, 2013·ELife·Maria Gutierrez-ArcelusEmmanouil T Dermitzakis
Dec 5, 2009·Genome Biology·Yingying ZhangAlbert Jeltsch
Sep 22, 2010·Human Molecular Genetics·Benjamin Tycko
Mar 1, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shuguang LengSteven A Belinsky
Jan 24, 2013·Briefings in Functional Genomics·Duncan Sproul, Richard R Meehan
Aug 9, 2011·Genetics and Molecular Research : GMR·A M da SilvaE S Ramos
May 30, 2012·Nature Reviews. Genetics·Peter A Jones
Aug 26, 2014·Neuroscience Research·Jerry Guintivano, Zachary A Kaminsky
Oct 29, 2015·Epigenetics : Official Journal of the DNA Methylation Society·Laura WeddRyszard Maleszka
Feb 14, 2013·Current Opinion in Cell Biology·Saher Sue HammoudDavid A Jones
Apr 3, 2010·Current Opinion in Genetics & Development·Luke B HessonRobyn L Ward
Oct 7, 2008·The International Journal of Biochemistry & Cell Biology·Alexander Dobrovic, Lasse S Kristensen
Sep 30, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Robert ShoemakerKun Zhang
May 11, 2012·International Journal of Cancer. Journal International Du Cancer·Michael KlothWolfgang A Schulz
Oct 21, 2010·CA: a Cancer Journal for Clinicians·Rodolphe Taby, Jean-Pierre J Issa
Feb 5, 2010·International Journal of Cancer. Journal International Du Cancer·Byonggu AnYoshitaka Sekido
Apr 19, 2015·Genetics, Selection, Evolution : GSE·Jordi CorominasMaria Ballester
Jun 21, 2017·Genome Biology·Catherine DoBenjamin Tycko
Jan 5, 2018·Oncotarget·Na DengYuan Yuan
Jul 31, 2020·BMC Genetics·Manthan PatelUmashankar Singh
Jul 22, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Queralt Seguín-EstévezWalter Reith
Sep 7, 2012·Molecular Cancer Research : MCR·Marcos R H EstécioJean-Pierre J Issa
Oct 30, 2020·Cancers·Magdalena GebertRafał Bartoszewski
Jun 13, 2021·Nature Communications·Thomas DahletMichael Weber

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Methods Mentioned

BETA
MDS
PCR
electrophoretic mobility shift
transfections
transfection
deamination
protein assay
Assay

Software Mentioned

Quantity One
COBRA
MatInspector
Primer Express
Excel
PSQ HS96A
Graphpad Prizm
Transfac

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