Epigenetic marks on the chromatin are associated with RNA splicing in human leukemia cells
Keywords:
epigenetic marks, alternative splicing, leukemiaAbstract
In this work we estimated associations between distribution patterns of several epigenetic marks and splicing events on the level of full genome and transcriptome in the cells of two leukemic cell lines containing two different reciprocal chromosome translocations. Significant difference in distribution of epigenetic marks was found, contributing to more opened or more closed chromatin in loci of donor vs acceptor and canonical vs alternative splice sites in expressing genes. Marks of the opened chromatin are significantly more often present in the genomic regions with alternative splicing events than in regions with canonical splicing, while for the mark of the histone 3 trimethylation at lysine 36, the opposite trend is observed. The obtained results reveal the presence of an additional, still very poorly studied layer in the regulation of alternative splicing in human cells.
References
- Hyung D, Kim J, Cho SY, Park C. ASpedia: a comprehensive encyclopedia of human alternative splicing. Nucleic Acids Research. 2018 January 4;46(D1):D58–D63. DOI: 10.1093/nar/gkx1014.
- Ramanouskaya TV, Grinev VV. The determinants of alternative RNA splicing in human cells. Molecular Genetics and Genomics. 2017 December;292(6):1175–1195. DOI: 10.1007/s00438-017-1350-0.
- Grinev V, Ilyushonak I, Clough R, Nakjang S, Smink J, Martinez-Soria N, et al. RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells. BioRxiv 628040 [Preprint]. 2019 [cited 2019 February 1]: [36 p.]. Available from: https://doi.org/10.1101/628040.
- Listerman I, Sapra AK, Neugebauer KM. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nature Structural & Molecular Biology. 2006 October;13(9):815–822. DOI: 10.1038/nsmb1135.
- Veloso A, Kirkconnell KS, Magnuson B, Biewen B, Paulsen MT, Wilson TE, et al. Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications. Genome Research. 2014;24:896–905. DOI: 10.1101/gr.171405.113.
- Iwamori N, Tominaga K, Sato T, Riehle K, Iwamori T, Ohkawa Ya, et al. MRG15 is required for pre-mRNA splicing and spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2016 September 13;113(37):E5408–E5415. DOI: 10.1073/pnas.1611995113.
- Sanidas I, Polytarchou C, Hatziapostolou M, Ezell SA, Kottakis F, Hu L, et al. Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer. Molecular Cell. 2014 February 20;53(4):577–590. DOI: 10.1016/j.molcel.2013.12.018.
- Kouwe E, Staber PhB. RUNX1-ETO: attacking the epigenome for genomic instable leukemia. International Journal of Molecular Sciences. 2019;20(2):350. DOI: 10.3390/ijms20020350.
- Kerry J, Godfrey L, Repapi E, Tapia M, Blackledge NP, Ma H, et al. MLL-AF4 spreading identifies binding sites that are distinct from super-enhancers and that govern sensitivity to DOT1L inhibition in leukemia. Cell Reports. 2017 January 10;18(2):482– 495. DOI: 10.1016/j.celrep.2016.12.054.
- Grinev VV, Heidenreich O. The knockdown of the fusion oncogene KMT2A-AFF1 is associated with differential RNA splicing in human acute lymphoblastic leukemia cells. Journal of the Belarusian State University. Biology. 2017;3:21–27. Russian.
- Ptasinska A, Assi SA, Mannari D, James SR, Williamson D, Dunne J, et al. Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding. Leukemia. 2012;26(8):1829–1841. DOI: 10.1038/leu.2012.49.
- Liao Y, Smyth GK, Shi W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Research. 2013 May 1;41(10):e108. DOI: 10.1093/nar/gkt214.
- Grinev VV. Intron retention in the transcriptome of leukemic and normal human blood cells. Molekulyarnaya i prikladnaya genetika. 2018;25:44 –55. Russian.
- Benito JM, Godfrey L, Kojima K, Hogda L, Wunderlich M, Geng H, et al. MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199. Cell Reports. 2015 December 29;13(12):2715–2727. DOI: 10.1016/j.celrep.2015.12.003.
- Lawrence M, Huber W, Pagès H, Aboyoun P, Carlson M, Gentleman R, et al. Software for Computing and Annotating Genomic Ranges. PLOS Computational Biology. 2013;9(8):e1003118. DOI: 10.1371/journal.pcbi.1003118.
- Li T, Liu Q, Garza N, Kornblau S, Jin VX. Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing. Genome Medicine. 2018;10:30. DOI: 10.1186/s13073-018-0538-1.
Downloads
Additional Files
Published
Issue
Section
License
The authors who are published in this journal agree to the following:
- The authors retain copyright on the work and provide the journal with the right of first publication of the work on condition of license Creative Commons Attribution-NonCommercial. 4.0 International (CC BY-NC 4.0).
- The authors retain the right to enter into certain contractual agreements relating to the non-exclusive distribution of the published version of the work (e.g. post it on the institutional repository, publication in the book), with the reference to its original publication in this journal.
- The authors have the right to post their work on the Internet (e.g. on the institutional store or personal website) prior to and during the review process, conducted by the journal, as this may lead to a productive discussion and a large number of references to this work. (See The Effect of Open Access.)










