PHF2 Histone Demethylase Prevents DNA Damage and Genome Instability by Controlling Cell Cycle Progression of Neural Progenitors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Sep 7

PMID 31488723

Citations 28

Authors

Stella Pappa

Natalia Padilla

Simona Iacobucci

Marta Vicioso

Elena Alvarez de la Campa

Claudia Navarro

Elia Marcos

Xavier de la Cruz

Marian A Martinez-Balbas

Affiliations

Soon will be listed here.

Abstract

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

Citing Articles

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References

Helmrich A, Ballarino M, Tora L . Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell. 2011; 44(6):966-77. DOI: 10.1016/j.molcel.2011.10.013. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Lee C, Kim B, Song B, Moon K . Implication of PHF2 Expression in Clear Cell Renal Cell Carcinoma. J Pathol Transl Med. 2017; 51(4):359-364. PMC: 5525036. DOI: 10.4132/jptm.2017.03.16. View

Blanco-Garcia N, Asensio-Juan E, de la Cruz X, Martinez-Balbas M . Autoacetylation regulates P/CAF nuclear localization. J Biol Chem. 2008; 284(3):1343-52. DOI: 10.1074/jbc.M806075200. View

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

Kim H, Park J, Lee K, Yoon H, Shin D, Ju U . Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation. Cell Res. 2014; 24(10):1231-49. PMC: 4185351. DOI: 10.1038/cr.2014.127. View

Okuno Y, Ohtake F, Igarashi K, Kanno J, Matsumoto T, Takada I . Epigenetic regulation of adipogenesis by PHF2 histone demethylase. Diabetes. 2013; 62(5):1426-34. PMC: 3636657. DOI: 10.2337/db12-0628. View

Currle D, Hu J, Kolski-Andreaco A, Monuki E . Culture of mouse neural stem cell precursors. J Vis Exp. 2008; (2):152. PMC: 2532938. DOI: 10.3791/152. View

Young L, McDonald D, Hendzel M . Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following γ-irradiation. J Biol Chem. 2013; 288(29):21376-21388. PMC: 3774405. DOI: 10.1074/jbc.M113.491514. View

10.

Sollier J, Cimprich K . Breaking bad: R-loops and genome integrity. Trends Cell Biol. 2015; 25(9):514-22. PMC: 4554970. DOI: 10.1016/j.tcb.2015.05.003. View

11.

Tiberi L, Vanderhaeghen P, van den Ameele J . Cortical neurogenesis and morphogens: diversity of cues, sources and functions. Curr Opin Cell Biol. 2012; 24(2):269-76. DOI: 10.1016/j.ceb.2012.01.010. View

12.

Akizu N, Garcia M, Estaras C, Fueyo R, Badosa C, de la Cruz X . EZH2 regulates neuroepithelium structure and neuroblast proliferation by repressing p21. Open Biol. 2016; 6(4):150227. PMC: 4852452. DOI: 10.1098/rsob.150227. View

13.

Nicholson G, Dawkins J, Blair I, Kennerson M, Gordon M, Cherryson A . The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3. Nat Genet. 1996; 13(1):101-4. DOI: 10.1038/ng0596-101. View

14.

Zheng H, Chen L, Pledger W, Fang J, Chen J . p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression. Oncogene. 2013; 33(6):734-44. PMC: 3912226. DOI: 10.1038/onc.2013.6. View

15.

Nakayama J, Rice J, Strahl B, Allis C, Grewal S . Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001; 292(5514):110-3. DOI: 10.1126/science.1060118. View

16.

Bernier R, Golzio C, Xiong B, Stessman H, Coe B, Penn O . Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014; 158(2):263-276. PMC: 4136921. DOI: 10.1016/j.cell.2014.06.017. View

17.

Wen H, Li J, Song T, Lu M, Kan P, Lee M . Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation. J Biol Chem. 2010; 285(13):9322-9326. PMC: 2843180. DOI: 10.1074/jbc.C109.097667. View

18.

Epsztejn-Litman S, Feldman N, Abu-Remaileh M, Shufaro Y, Gerson A, Ueda J . De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat Struct Mol Biol. 2008; 15(11):1176-1183. PMC: 2581722. DOI: 10.1038/nsmb.1476. View

19.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

20.

Cotney J, Muhle R, Sanders S, Liu L, Willsey A, Niu W . The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun. 2015; 6:6404. PMC: 4355952. DOI: 10.1038/ncomms7404. View