Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres

Maheshi I K Udugama, T M Fiona Chang, F Lyn Chan, Michelle C Tang, Hilda A Pickett, James D R McGhie, Lynne Mayne, Phillipe Collas, Jeffrey R Mann, Lee Hwa Hwa Wong

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Abstract

In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a-/- and H3f3b-/- mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b-/- cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b-/- cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.
Original languageEnglish
Pages (from-to)10227 - 10237
Number of pages11
JournalNucleic Acids Research
Volume43
Issue number21
DOIs
Publication statusPublished - 2015

Cite this

Udugama, M. I. K., Chang, T. M. F., Chan, F. L., Tang, M. C., Pickett, H. A., McGhie, J. D. R., ... Wong, L. H. H. (2015). Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. Nucleic Acids Research, 43(21), 10227 - 10237. https://doi.org/10.1093/nar/gkv847
Udugama, Maheshi I K ; Chang, T M Fiona ; Chan, F Lyn ; Tang, Michelle C ; Pickett, Hilda A ; McGhie, James D R ; Mayne, Lynne ; Collas, Phillipe ; Mann, Jeffrey R ; Wong, Lee Hwa Hwa. / Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 21. pp. 10227 - 10237.
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abstract = "In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a-/- and H3f3b-/- mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b-/- cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b-/- cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.",
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Udugama, MIK, Chang, TMF, Chan, FL, Tang, MC, Pickett, HA, McGhie, JDR, Mayne, L, Collas, P, Mann, JR & Wong, LHH 2015, 'Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres', Nucleic Acids Research, vol. 43, no. 21, pp. 10227 - 10237. https://doi.org/10.1093/nar/gkv847

Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. / Udugama, Maheshi I K; Chang, T M Fiona; Chan, F Lyn; Tang, Michelle C; Pickett, Hilda A; McGhie, James D R; Mayne, Lynne; Collas, Phillipe; Mann, Jeffrey R; Wong, Lee Hwa Hwa.

In: Nucleic Acids Research, Vol. 43, No. 21, 2015, p. 10227 - 10237.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Udugama, Maheshi I K

AU - Chang, T M Fiona

AU - Chan, F Lyn

AU - Tang, Michelle C

AU - Pickett, Hilda A

AU - McGhie, James D R

AU - Mayne, Lynne

AU - Collas, Phillipe

AU - Mann, Jeffrey R

AU - Wong, Lee Hwa Hwa

PY - 2015

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N2 - In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a-/- and H3f3b-/- mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b-/- cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b-/- cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.

AB - In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a-/- and H3f3b-/- mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b-/- cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b-/- cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666390/pdf/gkv847.pdf

U2 - 10.1093/nar/gkv847

DO - 10.1093/nar/gkv847

M3 - Article

VL - 43

SP - 10227

EP - 10237

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

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Udugama MIK, Chang TMF, Chan FL, Tang MC, Pickett HA, McGhie JDR et al. Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. Nucleic Acids Research. 2015;43(21):10227 - 10237. https://doi.org/10.1093/nar/gkv847