Histone H1.5 Binds over Splice Sites in Chromatin and Regulates Alternative Splicing

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2019 May 12

PMID 31076740

Citations 8

Authors

Ohad Glaich

Yodfat Leader

Galit Lev Maor

Gil Ast

Affiliations

Soon will be listed here.

Abstract

Chromatin organization and epigenetic markers influence splicing, though the magnitudes of these effects and the mechanisms are largely unknown. Here, we demonstrate that linker histone H1.5 influences mRNA splicing. We observed that linker histone H1.5 binds DNA over splice sites of short exons in human lung fibroblasts (IMR90 cells). We found that association of H1.5 with these splice sites correlated with the level of inclusion of alternatively spliced exons. Exons marked by H1.5 had more RNA polymerase II (RNAP II) stalling near the 3' splice site than did exons not associated with H1.5. In cells depleted of H1.5, we showed that the inclusion of five exons evaluated decreased and that RNAP II levels over these exons were also reduced. Our findings indicate that H1.5 is involved in regulation of splice site selection and alternative splicing, a function not previously demonstrated for linker histones.

Citing Articles

Structural basis of RNA polymerase II transcription on the chromatosome containing linker histone H1.

Hirano R, Ehara H, Kujirai T, Uejima T, Takizawa Y, Sekine S Nat Commun. 2022; 13(1):7287.

PMID: 36435862 PMC: 9701232. DOI: 10.1038/s41467-022-35003-z.

Histone Marks-Dependent Effect on Alternative Splicing: New Perspectives for Targeted Splicing Modulation in Cancer?.

Imbriano C, Belluti S Int J Mol Sci. 2022; 23(15).

PMID: 35955433 PMC: 9368390. DOI: 10.3390/ijms23158304.

COVID-19 Infection During Pregnancy Induces Differential Gene Expression in Human Cord Blood Cells From Term Neonates.

Gayen Nee Betal S, Urday P, Al-Kouatly H, Solarin K, Chan J, Addya S Front Pediatr. 2022; 10:834771.

PMID: 35547542 PMC: 9084610. DOI: 10.3389/fped.2022.834771.

Histone variants at a glance.

Talbert P, Henikoff S J Cell Sci. 2021; 134(6).

PMID: 33771851 PMC: 8015243. DOI: 10.1242/jcs.244749.

Short H2A histone variants are expressed in cancer.

Chew G, Bleakley M, Bradley R, Malik H, Henikoff S, Molaro A Nat Commun. 2021; 12(1):490.

PMID: 33473122 PMC: 7817690. DOI: 10.1038/s41467-020-20707-x.

References

Maunakea A, Chepelev I, Cui K, Zhao K . Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 2013; 23(11):1256-69. PMC: 3817542. DOI: 10.1038/cr.2013.110. View

Kornblihtt A, Schor I, Allo M, Blencowe B . When chromatin meets splicing. Nat Struct Mol Biol. 2009; 16(9):902-3. DOI: 10.1038/nsmb0909-902. View

Millan-Arino L, Islam A, Izquierdo-Bouldstridge A, Mayor R, Terme J, Luque N . Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2. Nucleic Acids Res. 2014; 42(7):4474-93. PMC: 3985652. DOI: 10.1093/nar/gku079. View

Kulaeva O, Hsieh F, Chang H, Luse D, Studitsky V . Mechanism of transcription through a nucleosome by RNA polymerase II. Biochim Biophys Acta. 2012; 1829(1):76-83. PMC: 3535581. DOI: 10.1016/j.bbagrm.2012.08.015. View

Spiluttini B, Gu B, Belagal P, Smirnova A, Nguyen V, Hebert C . Splicing-independent recruitment of U1 snRNP to a transcription unit in living cells. J Cell Sci. 2010; 123(Pt 12):2085-93. DOI: 10.1242/jcs.061358. View

Hergeth S, Schneider R . The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle. EMBO Rep. 2015; 16(11):1439-53. PMC: 4641498. DOI: 10.15252/embr.201540749. View

Li J, Patterson M, Mikkola H, Lowry W, Kurdistani S . Dynamic distribution of linker histone H1.5 in cellular differentiation. PLoS Genet. 2012; 8(8):e1002879. PMC: 3431313. DOI: 10.1371/journal.pgen.1002879. View

Mata M, Alonso C, Kadener S, Fededa J, Blaustein M, Pelisch F . A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell. 2003; 12(2):525-32. DOI: 10.1016/j.molcel.2003.08.001. View

Das R, Yu J, Zhang Z, Gygi M, Krainer A, Gygi S . SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol Cell. 2007; 26(6):867-81. DOI: 10.1016/j.molcel.2007.05.036. View

10.

Sakharkar M, Chow V, Kangueane P . Distributions of exons and introns in the human genome. In Silico Biol. 2004; 4(4):387-93. View

11.

Luco R, Misteli T . More than a splicing code: integrating the role of RNA, chromatin and non-coding RNA in alternative splicing regulation. Curr Opin Genet Dev. 2011; 21(4):366-72. PMC: 6317717. DOI: 10.1016/j.gde.2011.03.004. View

12.

Tillo D, Hughes T . G+C content dominates intrinsic nucleosome occupancy. BMC Bioinformatics. 2009; 10:442. PMC: 2808325. DOI: 10.1186/1471-2105-10-442. View

13.

Tilgner H, Guigo R . From chromatin to splicing: RNA-processing as a total artwork. Epigenetics. 2010; 5(3):180-4. DOI: 10.4161/epi.5.3.11319. View

14.

Daujat S, Zeissler U, Waldmann T, Happel N, Schneider R . HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding. J Biol Chem. 2005; 280(45):38090-5. DOI: 10.1074/jbc.C500229200. View

15.

Fan Y, Nikitina T, Zhao J, Fleury T, Bhattacharyya R, Bouhassira E . Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell. 2005; 123(7):1199-212. DOI: 10.1016/j.cell.2005.10.028. View

16.

Ziller M, Gu H, Muller F, Donaghey J, Tsai L, Kohlbacher O . Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013; 500(7463):477-81. PMC: 3821869. DOI: 10.1038/nature12433. View

17.

Harshman S, Young N, Parthun M, Freitas M . H1 histones: current perspectives and challenges. Nucleic Acids Res. 2013; 41(21):9593-609. PMC: 3834806. DOI: 10.1093/nar/gkt700. View

18.

Pennings S, Meersseman G, Bradbury E . Linker histones H1 and H5 prevent the mobility of positioned nucleosomes. Proc Natl Acad Sci U S A. 1994; 91(22):10275-9. PMC: 45002. DOI: 10.1073/pnas.91.22.10275. View

19.

Carmel I, Tal S, Vig I, Ast G . Comparative analysis detects dependencies among the 5' splice-site positions. RNA. 2004; 10(5):828-40. PMC: 1370573. DOI: 10.1261/rna.5196404. View

20.

Shapiro M, Senapathy P . RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987; 15(17):7155-74. PMC: 306199. DOI: 10.1093/nar/15.17.7155. View