Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 10227 - 10237 |
| Number of pages | 11 |
| Journal | Nucleic Acids Research |
| Volume | 43 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - 2015 |
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres
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
Y1 - 2015
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
IS - 21
ER -