TY - JOUR
T1 - Tet2 Catalyzes Stepwise 5-Methylcytosine Oxidation by an Iterative and de novo Mechanism
AU - Crawford, Daniel J.
AU - Liu, Monica Yun
AU - Nabel, Christopher S.
AU - Cao, Xing Jun
AU - Garcia, Benjamin A.
AU - Kohli, Rahul M.
N1 - Funding Information:
This work was supported by the Rita Allen Foundation Scholar Award (R.M.K.) and NIH grants (R01GM110174, B.A.G.; F30CA196097, M.Y.L.).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/1/27
Y1 - 2016/1/27
N2 - Modification of cytosine-guanine dinucleotides (CpGs) is a key part of mammalian epigenetic regulation and helps shape cellular identity. Tet enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) in CpGs to 5-hydroxymethylcytosine (hmC), or onward to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). The multiple mC oxidation products, while intricately linked, are postulated to play independent epigenetic roles, making it critical to understand how the products of stepwise oxidation are established and maintained. Using highly sensitive isotope-based studies, we newly show that Tet2 can yield fC and caC by iteratively acting in a single encounter with mC-containing DNA, without release of the hmC intermediate, and that the modification state of the complementary CpG has little impact on Tet2 activity. By revealing Tet2 as an iterative, de novo mC oxygenase, our study provides insight into how features intrinsic to Tet2 shape the epigenetic landscape.
AB - Modification of cytosine-guanine dinucleotides (CpGs) is a key part of mammalian epigenetic regulation and helps shape cellular identity. Tet enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) in CpGs to 5-hydroxymethylcytosine (hmC), or onward to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). The multiple mC oxidation products, while intricately linked, are postulated to play independent epigenetic roles, making it critical to understand how the products of stepwise oxidation are established and maintained. Using highly sensitive isotope-based studies, we newly show that Tet2 can yield fC and caC by iteratively acting in a single encounter with mC-containing DNA, without release of the hmC intermediate, and that the modification state of the complementary CpG has little impact on Tet2 activity. By revealing Tet2 as an iterative, de novo mC oxygenase, our study provides insight into how features intrinsic to Tet2 shape the epigenetic landscape.
UR - http://www.scopus.com/inward/record.url?scp=84956811348&partnerID=8YFLogxK
U2 - 10.1021/jacs.5b10554
DO - 10.1021/jacs.5b10554
M3 - Article
C2 - 26734843
AN - SCOPUS:84956811348
SN - 0002-7863
VL - 138
SP - 730
EP - 733
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 3
ER -