A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Schizosaccharomyces*/genetics ; Schizosaccharomyces*/metabolism ; Heterochromatin*/metabolism ; Heterochromatin*/genetics ; Schizosaccharomyces pombe Proteins*/metabolism ; Schizosaccharomyces pombe Proteins*/genetics ; Gene Expression Regulation, Fungal*; Gene Silencing ; Mutation ; Histones/metabolism ; Histones/genetics ; Telomere/metabolism ; Telomere/genetics ; Centromere/metabolism ; Centromere/genetics ; Methylation

Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in delayed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Update of: bioRxiv. 2024 Feb 15:2024.02.13.579970. doi: 10.1101/2024.02.13.579970. (PMID: 38405799)

Nat Rev Genet. 2015 Feb;16(2):71-84. (PMID: 25554358)
Mol Cell. 2020 Jan 2;77(1):51-66.e8. (PMID: 31784357)
Cell. 2004 Dec 17;119(6):789-802. (PMID: 15607976)
MicroPubl Biol. 2023 Jul 6;2023:. (PMID: 37485020)
Mol Cell. 2017 Jul 20;67(2):294-307.e9. (PMID: 28648780)
Cell. 2007 Feb 9;128(3):491-504. (PMID: 17289569)
Cell. 2012 Aug 31;150(5):934-47. (PMID: 22939621)
Science. 2015 Apr 3;348(6230):132-5. (PMID: 25838386)
G3 (Bethesda). 2018 Feb 2;8(2):477-489. (PMID: 29187422)
Genes Cells. 2013 Apr;18(4):327-39. (PMID: 23388053)
J Biol Chem. 2004 Oct 8;279(41):42850-9. (PMID: 15292231)
PLoS Genet. 2013;9(1):e1003213. (PMID: 23349636)
J Mol Biol. 2014 Jan 23;426(2):301-8. (PMID: 24144619)
Genetics. 2005 Dec;171(4):1583-95. (PMID: 16157682)
Cell Metab. 2015 Nov 3;22(5):861-73. (PMID: 26411344)
Nature. 2018 Jun;558(7711):615-619. (PMID: 29925950)
Genome Biol. 2014;15(10):481. (PMID: 25274039)
EMBO J. 2018 Jan 4;37(1):89-101. (PMID: 28947618)
Genome Biol. 2010;11(6):R60. (PMID: 20537132)
Elife. 2018 Jul 18;7:. (PMID: 30020075)
Nature. 1998 Apr 23;392(6678):825-8. (PMID: 9572142)
PLoS Genet. 2014 May 29;10(5):e1004334. (PMID: 24874881)
EMBO Rep. 2016 Feb;17(2):139-55. (PMID: 26792937)
Wellcome Open Res. 2020 Nov 24;5:274. (PMID: 33313420)
Nucleic Acids Res. 2014 Oct;42(18):11419-32. (PMID: 25245948)
Science. 2004 Jun 25;304(5679):1971-6. (PMID: 15218150)
Nat Genet. 2004 Nov;36(11):1174-80. (PMID: 15475954)
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8276-82. (PMID: 11459964)
Nature. 2011 Jul 03;475(7355):244-8. (PMID: 21725325)
Proc Natl Acad Sci U S A. 2024 Feb 6;121(6):e2315596121. (PMID: 38285941)
Genes Cells. 2024 Dec;29(12):1207-1224. (PMID: 39473172)
RNA Biol. 2005 Jul-Sep;2(3):106-11. (PMID: 17114925)
Science. 2001 Apr 6;292(5514):110-3. (PMID: 11283354)
Nat Struct Mol Biol. 2011 Sep 04;18(10):1132-8. (PMID: 21892171)
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11258-63. (PMID: 22733737)
Biochem Biophys Res Commun. 2006 Nov 10;350(1):125-30. (PMID: 16997270)
Cold Spring Harb Perspect Biol. 2015 Jul 01;7(7):a018770. (PMID: 26134317)
Nature. 2020 Jan;577(7792):717-720. (PMID: 31969703)
J Biochem. 2023 Jun 30;174(1):33-46. (PMID: 36799444)
Nat Commun. 2016 Jan 25;7:10393. (PMID: 26804021)
Yeast. 2004 Aug;21(11):947-62. (PMID: 15334558)
Science. 2012 Jul 13;337(6091):243-5. (PMID: 22678361)
EMBO J. 2009 Dec 2;28(23):3693-705. (PMID: 19910927)
Nucleic Acids Res. 2022 Sep 23;50(17):10000-10014. (PMID: 36095128)
Cell. 2011 Jan 7;144(1):41-54. (PMID: 21215368)
Nat Cell Biol. 2021 Aug;23(8):905-914. (PMID: 34354237)
G3 (Bethesda). 2022 Jul 6;12(7):. (PMID: 35567482)
Nature. 2015 Apr 9;520(7546):248-252. (PMID: 25807481)
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6159-64. (PMID: 22474355)
Mol Cell Biol. 2005 Jan;25(2):590-601. (PMID: 15632061)
Front Genet. 2015 Nov 16;6:330. (PMID: 26635866)
Nat Struct Mol Biol. 2020 Aug;27(8):735-742. (PMID: 32632277)
Mol Cell. 2024 Sep 5;84(17):3223-3236.e4. (PMID: 39094566)
Mol Cell. 2017 Apr 6;66(1):50-62.e6. (PMID: 28318821)
Genes Dev. 2016 Jan 15;30(2):133-48. (PMID: 26744419)
Cell. 2018 Aug 23;174(5):1117-1126.e12. (PMID: 30100186)
EMBO Rep. 2015 Dec;16(12):1673-87. (PMID: 26518661)
RNA. 2014 Jun;20(6):867-81. (PMID: 24713849)
Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
Genetics. 1996 Jun;143(2):887-96. (PMID: 8725236)
Nature. 1997 Feb 20;385(6618):744-7. (PMID: 9034194)
Mol Cell. 2006 Jun 9;22(5):681-92. (PMID: 16762840)
J Exp Med. 2010 Dec 20;207(13):2817-30. (PMID: 21098095)
Nat Rev Mol Cell Biol. 2018 Apr;19(4):229-244. (PMID: 29235574)
Genetics. 1999 Nov;153(3):1153-69. (PMID: 10545449)
Nat Struct Mol Biol. 2022 Sep;29(9):910-921. (PMID: 36123402)
Nucleic Acids Res. 2023 Jan 6;51(D1):D638-D646. (PMID: 36370105)
Nature. 2001 Mar 1;410(6824):120-4. (PMID: 11242054)
J Biol Chem. 2012 Feb 3;287(6):4386-93. (PMID: 22184112)
Elife. 2020 Jun 03;9:. (PMID: 32491985)
iScience. 2018 Jul 27;5:38-51. (PMID: 30240645)
EMBO J. 2005 Nov 16;24(22):3940-51. (PMID: 16252005)
Cell. 2020 Jan 9;180(1):150-164.e15. (PMID: 31883795)
Sci Rep. 2015 Oct 07;5:14707. (PMID: 26443059)
Methods Enzymol. 2010;470:145-79. (PMID: 20946810)
Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):. (PMID: 34035174)
Genes Dev. 2005 Jul 15;19(14):1705-14. (PMID: 16024659)
Mol Cell. 2008 Dec 26;32(6):778-90. (PMID: 19111658)
Cell. 2024 Sep 5;187(18):5029-5047.e21. (PMID: 39094569)
J Cell Sci. 2023 Dec 1;136(23):. (PMID: 37970674)
Genes Cells. 2016 Aug;21(8):812-32. (PMID: 27334362)
PLoS One. 2016 Aug 01;11(8):e0159292. (PMID: 27479698)
Science. 2004 Jan 30;303(5658):672-6. (PMID: 14704433)
EMBO Rep. 2016 Jan;17(1):79-93. (PMID: 26582768)
Elife. 2021 Sep 15;10:. (PMID: 34524082)
Nat Struct Mol Biol. 2008 Apr;15(4):381-8. (PMID: 18345014)
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):152-7. (PMID: 15615848)
Science. 2015 Apr 3;348(6230):1258699. (PMID: 25831549)
Nucleic Acids Res. 1993 Dec 25;21(25):5940-4. (PMID: 8290356)
Science. 2012 Jan 6;335(6064):96-100. (PMID: 22144463)
Cell Mol Life Sci. 2014 Dec;71(24):4841-52. (PMID: 25192661)
Nat Cell Biol. 2005 Oct;7(10):1007-13. (PMID: 16127433)
Science. 2012 Jul 13;337(6091):195-9. (PMID: 22678362)
EMBO Rep. 2019 Oct 4;20(10):e48111. (PMID: 31468675)
Nucleic Acids Res. 2006 Jan 10;34(1):78-88. (PMID: 16407326)
Cell. 2013 Nov 21;155(5):1061-74. (PMID: 24210919)
Curr Biol. 2005 Oct 25;15(20):1808-19. (PMID: 16243027)
Curr Biol. 2015 Aug 31;25(17):2254-9. (PMID: 26255844)
Mol Cell. 2016 Apr 21;62(2):207-221. (PMID: 27105116)
ACS Chem Biol. 2015 Jan 16;10(1):95-108. (PMID: 25562692)
Genetics. 2019 Sep;213(1):127-141. (PMID: 31278118)
Nucleic Acids Res. 2024 Aug 12;52(14):8286-8302. (PMID: 38917328)
J Cell Sci. 2019 May 15;132(10):. (PMID: 30975915)
Cell. 2010 Mar 5;140(5):666-77. (PMID: 20211136)
Nat Struct Mol Biol. 2007 Mar;14(3):200-7. (PMID: 17310250)
J Biol Chem. 2007 May 11;282(19):14065-72. (PMID: 17363370)
J Biol Chem. 2012 Jan 20;287(4):2652-65. (PMID: 22147691)
Genes Dev. 1995 Jan 15;9(2):218-33. (PMID: 7851795)
Mol Cell. 2023 Jun 1;83(11):1767-1785. (PMID: 37207657)
Nucleic Acids Res. 2020 Feb 20;48(3):1239-1253. (PMID: 31822915)
Front Genet. 2019 Aug 28;10:764. (PMID: 31555321)
Cell. 2024 Sep 5;187(18):5010-5028.e24. (PMID: 39094570)
Int J Mol Sci. 2021 Jan 11;22(2):. (PMID: 33440639)
Development. 2023 Nov 1;150(21):. (PMID: 37922125)
Mol Cell Biol. 2003 Jun;23(12):4356-70. (PMID: 12773576)
Mol Cell. 2010 Aug 13;39(3):360-72. (PMID: 20705239)
Nature. 2017 Jul 27;547(7664):463-467. (PMID: 28682306)
Genes Dev. 2009 Jan 1;23(1):18-23. (PMID: 19136623)
PLoS Genet. 2022 May 18;18(5):e1010201. (PMID: 35584134)
Genes Dev. 2012 Aug 15;26(16):1811-24. (PMID: 22895252)
Curr Biol. 2005 Aug 23;15(16):1448-57. (PMID: 16040243)
Microb Cell. 2020 Jan 03;7(3):80-92. (PMID: 32161768)
Open Biol. 2015 May;5(5):. (PMID: 25972440)
Mol Cell. 2016 Jun 16;62(6):862-874. (PMID: 27264871)
Mol Cell Biol. 2011 Oct;31(20):4193-204. (PMID: 21844224)
Genes Dev. 2013 Nov 15;27(22):2489-99. (PMID: 24240238)

2113319 National Science Foundation; HEALTH-2010-257082 FP7 Health; 860675 HORIZON EUROPE Marie Sklodowska-Curie Actions; R35 GM141888 United States GM NIGMS NIH HHS; ANR-21-CE11-0027 Agence Nationale de la Recherche; 464293512 Deutsche Forschungsgemeinschaft; R35GM141888 United States NH NIH HHS

0 (Heterochromatin)
0 (Schizosaccharomyces pombe Proteins)
0 (Histones)

Date Created: 20241120 Date Completed: 20241221 Latest Revision: 20250104

20250104

PMC11662645

10.1093/nar/gkae1024

39565189