Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma

Hanneke Vlaming; Chelsea M. McLean; Tessy Korthout; Mir Farshid Alemdehy; Sjoerd Hendriks; Cesare Lancini; Sander Palit; Sjoerd Klarenbeek; Eliza Mari Kwesi-Maliepaard; Thom M. Molenaar; Liesbeth Hoekman; Thierry T. Schmidlin; AF Maarten Altelaar; Tibor van Welsem; Jan Hermen Dannenberg; Heinz Jacobs; Fred van Leeuwen

doi:10.15252/embj.2019101564

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma

Hanneke Vlaming, Chelsea M. McLean, Tessy Korthout, Mir Farshid Alemdehy, Sjoerd Hendriks, Cesare Lancini, Sander Palit, Sjoerd Klarenbeek, Eliza Mari Kwesi-Maliepaard, Thom M. Molenaar, Liesbeth Hoekman, Thierry T. Schmidlin, AF Maarten Altelaar, Tibor van Welsem, Jan Hermen Dannenberg, Heinz Jacobs^*, Fred van Leeuwen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1^Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.

Original language	English
Article number	e101564
Number of pages	14
Journal	EMBO Journal
Volume	38
Issue number	14
DOIs	https://doi.org/10.15252/embj.2019101564
Publication status	Published - 15 Jul 2019

Funding

The authors thank Jeffrey McKnight and Toshio Tsukiyama for sharing Rpd3 and H4ac ChIP-seq data. We thank Roel Wilting and Marinus (Richard) Heideman for help with initial HDAC1 experiments, Michael Hauptman for statistical tests on the survival curves, Kevin Struhl for RPD3 plasmids, and Struan Murray and Jane Mellor for providing source data on antisense transcription. We thank the NKI animal pathology facility for histology and immunohistochemistry, as well as advice, the NKI Genomics Core Facility for library preparations and sequencing, the NKI FACS facility for assistance, Onno Bleijerveld for mass spectrometry advice, and the caretakers of the NKI laboratory animal facility for assistance and excellent animal care. We thank Ila van Kruijsbergen, Tineke Lenstra, and Maarten van Lohuizen for critically reading the manuscript. This work was supported by the Dutch Cancer Society (KWF2009-4511 and NKI2014-7232 to FvL and HJ) and the Netherlands Organisation for Scientific Research (NWO-VICI-016.130.627, NCI-KIEM-731.013.102, and NCI-LIFT-731.015.405 to FvL and ZonMW Top 91213018 to HJ). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Keywords

Chromatin
H3K79 methylation
histone acetylation
histone ubiquitination
lymphoma

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Vlaming, H., McLean, C. M., Korthout, T., Alemdehy, M. F., Hendriks, S., Lancini, C., Palit, S., Klarenbeek, S., Kwesi-Maliepaard, E. M., Molenaar, T. M., Hoekman, L., Schmidlin, T. T., Altelaar, AF. M., van Welsem, T., Dannenberg, J. H., Jacobs, H., & van Leeuwen, F. (2019). Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma. EMBO Journal, 38(14), Article e101564. https://doi.org/10.15252/embj.2019101564

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title = "Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma",

abstract = "DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.",

keywords = "Chromatin, H3K79 methylation, histone acetylation, histone ubiquitination, lymphoma",

author = "Hanneke Vlaming and McLean, {Chelsea M.} and Tessy Korthout and Alemdehy, {Mir Farshid} and Sjoerd Hendriks and Cesare Lancini and Sander Palit and Sjoerd Klarenbeek and Kwesi-Maliepaard, {Eliza Mari} and Molenaar, {Thom M.} and Liesbeth Hoekman and Schmidlin, {Thierry T.} and Altelaar, {AF Maarten} and {van Welsem}, Tibor and Dannenberg, {Jan Hermen} and Heinz Jacobs and {van Leeuwen}, Fred",

year = "2019",

month = jul,

day = "15",

doi = "10.15252/embj.2019101564",

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Vlaming, H, McLean, CM, Korthout, T, Alemdehy, MF, Hendriks, S, Lancini, C, Palit, S, Klarenbeek, S, Kwesi-Maliepaard, EM, Molenaar, TM, Hoekman, L, Schmidlin, TT, Altelaar, AFM, van Welsem, T, Dannenberg, JH, Jacobs, H & van Leeuwen, F 2019, 'Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma', EMBO Journal, vol. 38, no. 14, e101564. https://doi.org/10.15252/embj.2019101564

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T1 - Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma

AU - Vlaming, Hanneke

AU - McLean, Chelsea M.

AU - Korthout, Tessy

AU - Alemdehy, Mir Farshid

AU - Hendriks, Sjoerd

AU - Lancini, Cesare

AU - Palit, Sander

AU - Klarenbeek, Sjoerd

AU - Kwesi-Maliepaard, Eliza Mari

AU - Molenaar, Thom M.

AU - Hoekman, Liesbeth

AU - Schmidlin, Thierry T.

AU - Altelaar, AF Maarten

AU - van Welsem, Tibor

AU - Dannenberg, Jan Hermen

AU - Jacobs, Heinz

AU - van Leeuwen, Fred

PY - 2019/7/15

Y1 - 2019/7/15

N2 - DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.

AB - DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.

KW - Chromatin

KW - H3K79 methylation

KW - histone acetylation

KW - histone ubiquitination

KW - lymphoma

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DO - 10.15252/embj.2019101564

M3 - Article

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AN - SCOPUS:85067462981

SN - 0261-4189

VL - 38

JO - EMBO Journal

JF - EMBO Journal

IS - 14

M1 - e101564

ER -

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma

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Keywords

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