The Histone Methyltransferase KMT2B Is Required for RNA Polymerase II Association and Protection from DNA Methylation at the MagohB CpG Island Promoter

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The Histone Methyltransferase KMT2B Is Required for RNA Polymerase II Association and Protection from DNA Methylation at the MagohB CpG Island Promoter. / Ladopoulos, Vasileios; Hofemeister, Helmut; Hoogenkamp, Maarten; Riggs, Arthur D; Stewart, A Francis; Bonifer, Constanze.

In: Molecular and Cellular Biology, Vol. 33, No. 7, 04.2013, p. 1383-93.

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@article{2dcdf371b76843c698bc292048ac349b,
title = "The Histone Methyltransferase KMT2B Is Required for RNA Polymerase II Association and Protection from DNA Methylation at the MagohB CpG Island Promoter",
abstract = "KMT2B (MLL2/WBP7) is a member of the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal embryonic development in the mouse. To gain insight into the molecular mechanism underlying KMT2B function, we focused on MagohB, which is controlled by a CpG island promoter. We show that in cells lacking Mll2-the gene encoding KMT2B-the MagohB promoter resides in inaccessible chromatin and is methylated. To dissect the molecular events leading to the establishment of silencing, we performed kinetic studies in Mll2-conditional-knockout embryonic stem cells. KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated. We demonstrate that in the presence of KMT2B, neither transcription elongation nor RNA polymerase II binding is required to maintain H3K4 trimethylation at the MagohB promoter and protect it from DNA methylation. Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter. Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters.",
author = "Vasileios Ladopoulos and Helmut Hofemeister and Maarten Hoogenkamp and Riggs, {Arthur D} and Stewart, {A Francis} and Constanze Bonifer",
year = "2013",
month = apr,
doi = "10.1128/MCB.01721-12",
language = "English",
volume = "33",
pages = "1383--93",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "7",

}

RIS

TY - JOUR

T1 - The Histone Methyltransferase KMT2B Is Required for RNA Polymerase II Association and Protection from DNA Methylation at the MagohB CpG Island Promoter

AU - Ladopoulos, Vasileios

AU - Hofemeister, Helmut

AU - Hoogenkamp, Maarten

AU - Riggs, Arthur D

AU - Stewart, A Francis

AU - Bonifer, Constanze

PY - 2013/4

Y1 - 2013/4

N2 - KMT2B (MLL2/WBP7) is a member of the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal embryonic development in the mouse. To gain insight into the molecular mechanism underlying KMT2B function, we focused on MagohB, which is controlled by a CpG island promoter. We show that in cells lacking Mll2-the gene encoding KMT2B-the MagohB promoter resides in inaccessible chromatin and is methylated. To dissect the molecular events leading to the establishment of silencing, we performed kinetic studies in Mll2-conditional-knockout embryonic stem cells. KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated. We demonstrate that in the presence of KMT2B, neither transcription elongation nor RNA polymerase II binding is required to maintain H3K4 trimethylation at the MagohB promoter and protect it from DNA methylation. Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter. Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters.

AB - KMT2B (MLL2/WBP7) is a member of the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal embryonic development in the mouse. To gain insight into the molecular mechanism underlying KMT2B function, we focused on MagohB, which is controlled by a CpG island promoter. We show that in cells lacking Mll2-the gene encoding KMT2B-the MagohB promoter resides in inaccessible chromatin and is methylated. To dissect the molecular events leading to the establishment of silencing, we performed kinetic studies in Mll2-conditional-knockout embryonic stem cells. KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated. We demonstrate that in the presence of KMT2B, neither transcription elongation nor RNA polymerase II binding is required to maintain H3K4 trimethylation at the MagohB promoter and protect it from DNA methylation. Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter. Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters.

U2 - 10.1128/MCB.01721-12

DO - 10.1128/MCB.01721-12

M3 - Article

C2 - 23358417

VL - 33

SP - 1383

EP - 1393

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 7

ER -