A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer

Nucleic Acids Research
Charly R GoodJ P Issa

Abstract

TET1 oxidizes methylated cytosine into 5-hydroxymethylcytosine (5hmC), resulting in regulation of DNA methylation and gene expression. Full length TET1 (TET1FL) has a CXXC domain that binds to unmethylated CpG islands (CGIs). This CXXC domain allows TET1 to protect CGIs from aberrant methylation, but it also limits its ability to regulate genes outside of CGIs. Here, we report a novel isoform of TET1 (TET1ALT) that has a unique transcription start site from an alternate promoter in intron 2, yielding a protein with a unique translation start site. Importantly, TET1ALT lacks the CXXC domain but retains the catalytic domain. TET1ALT is repressed in embryonic stem cells (ESCs) but becomes activated in embryonic and adult tissues while TET1FL is expressed in ESCs, but repressed in adult tissues. Overexpression of TET1ALT shows production of 5hmC with distinct (and weaker) effects on DNA methylation or gene expression when compared to TET1FL. TET1ALT is aberrantly activated in multiple cancer types including breast, uterine and glioblastoma, and TET1 activation is associated with a worse overall survival in breast, uterine and ovarian cancers. Our data suggest that the predominantly activated isoform of TET1 in cancer cells does not...Continue Reading

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Citations

Apr 18, 2018·Chembiochem : a European Journal of Chemical Biology·Kosuke NishioHiroaki Suga
Oct 7, 2018·Epigenetics & Chromatin·Xinwei WuRuiyu Xie
Mar 21, 2018·Frontiers in Cell and Developmental Biology·Philippa MelamedLilach Pnueli
May 13, 2020·Cancer Metastasis Reviews·Alejandra I FerrerPranela Rameshwar
Jun 13, 2018·Cancer Research·Charly Ryan GoodJean-Pierre J Issa
Jan 4, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Peixing WanYehong Zhuo
Jan 26, 2021·The Journal of Biological Chemistry·Lin LiangZhongbo Yu
Dec 24, 2019·Journal of Molecular Biology·Cathia RauschM Cristina Cardoso
Jan 21, 2021·Trends in Cancer·Julie K BrayAnirban Maitra
Feb 20, 2021·Genomics, Proteomics & Bioinformatics·Gongwang YuJian-Rong Yang
Jul 3, 2021·Pharmaceuticals·Shoghag Panjarian, Jean-Pierre J Issa

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Datasets Mentioned

BETA
GSE93617
GSE93619
GM12878
MDA-MB-231

Methods Mentioned

BETA
protein assay
dot blot
Assay
transfection
PCR
RNA-seq
ChIP-seq
PCA

Software Mentioned

UCSC genome browser
Cuffdiff
BLAT
METABRIC
R
Encode
Serial Cloner
CBioPortal
TopHat2
Genomic Data Commons

Related Concepts