Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing

Andrew Keniry, Linden J. Gearing, Natasha Jansz, Joy Liu, Aliaksei Z. Holik, Peter F. Hickey, Sarah A. Kinkel, Darcy L Moore, Kelsey Breslin, Kelan Chen, Ruijie Liu, Catherine Phillips, Miha Pakusch, Christine Biben, Julie M. Sheridan, Benjamin T. Kile, Catherine Carmichael, Matthew E Ritchie, Douglas J. Hilton, Marnie E. Blewitt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. Results: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements. Conclusions: Here we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.

Original languageEnglish
Article number16
Number of pages20
JournalEpigenetics and Chromatin
Volume9
Issue number1
DOIs
Publication statusPublished - 18 May 2016
Externally publishedYes

Keywords

  • Epigenetic silencing
  • H3K9 methylation
  • Setdb1
  • X inactivation

Cite this

Keniry, A., Gearing, L. J., Jansz, N., Liu, J., Holik, A. Z., Hickey, P. F., ... Blewitt, M. E. (2016). Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing. Epigenetics and Chromatin, 9(1), [16]. https://doi.org/10.1186/s13072-016-0064-6
Keniry, Andrew ; Gearing, Linden J. ; Jansz, Natasha ; Liu, Joy ; Holik, Aliaksei Z. ; Hickey, Peter F. ; Kinkel, Sarah A. ; Moore, Darcy L ; Breslin, Kelsey ; Chen, Kelan ; Liu, Ruijie ; Phillips, Catherine ; Pakusch, Miha ; Biben, Christine ; Sheridan, Julie M. ; Kile, Benjamin T. ; Carmichael, Catherine ; Ritchie, Matthew E ; Hilton, Douglas J. ; Blewitt, Marnie E. / Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing. In: Epigenetics and Chromatin. 2016 ; Vol. 9, No. 1.
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title = "Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing",
abstract = "Background: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. Results: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements. Conclusions: Here we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.",
keywords = "Epigenetic silencing, H3K9 methylation, Setdb1, X inactivation",
author = "Andrew Keniry and Gearing, {Linden J.} and Natasha Jansz and Joy Liu and Holik, {Aliaksei Z.} and Hickey, {Peter F.} and Kinkel, {Sarah A.} and Moore, {Darcy L} and Kelsey Breslin and Kelan Chen and Ruijie Liu and Catherine Phillips and Miha Pakusch and Christine Biben and Sheridan, {Julie M.} and Kile, {Benjamin T.} and Catherine Carmichael and Ritchie, {Matthew E} and Hilton, {Douglas J.} and Blewitt, {Marnie E.}",
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Keniry, A, Gearing, LJ, Jansz, N, Liu, J, Holik, AZ, Hickey, PF, Kinkel, SA, Moore, DL, Breslin, K, Chen, K, Liu, R, Phillips, C, Pakusch, M, Biben, C, Sheridan, JM, Kile, BT, Carmichael, C, Ritchie, ME, Hilton, DJ & Blewitt, ME 2016, 'Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing' Epigenetics and Chromatin, vol. 9, no. 1, 16. https://doi.org/10.1186/s13072-016-0064-6

Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing. / Keniry, Andrew; Gearing, Linden J.; Jansz, Natasha; Liu, Joy; Holik, Aliaksei Z.; Hickey, Peter F.; Kinkel, Sarah A.; Moore, Darcy L; Breslin, Kelsey; Chen, Kelan; Liu, Ruijie; Phillips, Catherine ; Pakusch, Miha; Biben, Christine; Sheridan, Julie M.; Kile, Benjamin T.; Carmichael, Catherine; Ritchie, Matthew E; Hilton, Douglas J.; Blewitt, Marnie E.

In: Epigenetics and Chromatin, Vol. 9, No. 1, 16, 18.05.2016.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing

AU - Keniry, Andrew

AU - Gearing, Linden J.

AU - Jansz, Natasha

AU - Liu, Joy

AU - Holik, Aliaksei Z.

AU - Hickey, Peter F.

AU - Kinkel, Sarah A.

AU - Moore, Darcy L

AU - Breslin, Kelsey

AU - Chen, Kelan

AU - Liu, Ruijie

AU - Phillips, Catherine

AU - Pakusch, Miha

AU - Biben, Christine

AU - Sheridan, Julie M.

AU - Kile, Benjamin T.

AU - Carmichael, Catherine

AU - Ritchie, Matthew E

AU - Hilton, Douglas J.

AU - Blewitt, Marnie E.

PY - 2016/5/18

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N2 - Background: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. Results: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements. Conclusions: Here we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.

AB - Background: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. Results: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements. Conclusions: Here we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.

KW - Epigenetic silencing

KW - H3K9 methylation

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