CoTF-reg reveals cooperative transcription factors in oligodendrocyte gene regulation using single-cell multi-omics.

Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE

Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-

Oligodendroglia*/metabolism ; Transcription Factors*/metabolism ; Transcription Factors*/genetics ; Single-Cell Analysis*/methods ; Gene Expression Regulation*; Animals ; Mice ; Humans ; Multiomics

Oligodendrocytes are the myelinating cells within the central nervous system, but the mechanisms by which transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remain unclear. We introduce coTF-reg, an analytical framework that integrates scRNA-seq and scATAC-seq data to identify cooperative TFs co-regulating the target gene (TG). First, we identify co-binding TF pairs in the same oligodendrocyte-specific regulatory regions. Next, we train a deep learning model to predict each TG expression using the co-binding TFs' expressions. Shapley interaction scores reveal high interactions between co-binding TF pairs, such as SOX10-TCF12. Validation using oligodendrocyte eQTLs and their eGenes that are regulated by these cooperative TFs show potential regulatory roles for genetic variants. Experimental validation using ChIP-seq data confirms some cooperative TF pairs, such as SOX10-OLIG2. Prediction performance of our models is evaluated through holdout data and additional datasets, and an ablation study is also conducted. The results demonstrate stable and consistent performance.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)

Update of: bioRxiv. 2024 Jun 21:2024.06.19.599799. doi: 10.1101/2024.06.19.599799.. (PMID: 38948852)

Cell Rep. 2022 Oct 18;41(3):111480. (PMID: 36261002)
Dev Cell. 2015 Feb 23;32(4):447-58. (PMID: 25710531)
Cell. 2023 Sep 28;186(20):4365-4385.e27. (PMID: 37774677)
Acta Neuropathol Commun. 2023 Mar 31;11(1):56. (PMID: 37004127)
Glia. 2015 Nov;63(11):1897-1914. (PMID: 25974668)
Bioinformatics. 2017 Aug 01;33(15):2381-2383. (PMID: 28369316)
Nat Neurosci. 2024 Dec;27(12):2366-2383. (PMID: 39402379)
Acta Neuropathol Commun. 2018 Mar 2;6(1):22. (PMID: 29499767)
Cold Spring Harb Perspect Biol. 2015 Jun 22;8(1):a020479. (PMID: 26101081)
Nature. 2009 Sep 10;461(7261):186-92. (PMID: 19741698)
Nat Methods. 2021 Nov;18(11):1333-1341. (PMID: 34725479)
Dev Biol. 2007 Feb 15;302(2):683-93. (PMID: 17098222)
Bioinformatics. 2023 Feb 3;39(2):. (PMID: 36790055)
Nat Methods. 2023 Sep;20(9):1355-1367. (PMID: 37443338)
Nucleic Acids Res. 2017 May 19;45(9):5112-5125. (PMID: 28160598)
PLoS One. 2011;6(8):e22649. (PMID: 21853041)
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5136-41. (PMID: 12702751)
Genome Biol. 2022 Apr 19;23(1):100. (PMID: 35440087)
Science. 2024 May 24;384(6698):eadi5199. (PMID: 38781369)
PLoS Biol. 2013;11(8):e1001625. (PMID: 23966833)
Stem Cells. 2016 Aug;34(8):2115-29. (PMID: 27068685)
Cell Rep. 2017 Jan 10;18(2):314-323. (PMID: 28076777)
iScience. 2024 Feb 05;27(3):109124. (PMID: 38455978)
Nucleic Acids Res. 2024 Jan 5;52(D1):D154-D163. (PMID: 37971293)
Nat Rev Mol Cell Biol. 2015 Mar;16(3):144-54. (PMID: 25650801)
Cell. 2013 Jan 17;152(1-2):248-61. (PMID: 23332759)
Nucleic Acids Res. 2022 Nov 11;50(20):11509-11528. (PMID: 36318265)
Trends Neurosci. 2019 Apr;42(4):263-277. (PMID: 30770136)
Genome Biol. 2018 Feb 6;19(1):15. (PMID: 29409532)
Nat Neurosci. 2009 Jul;12(7):829-38. (PMID: 19503085)
Dev Neurobiol. 2021 Oct;81(7):892-901. (PMID: 34480425)
Glia. 2018 Feb;66(2):279-294. (PMID: 29023979)
Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119)
Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4914-E4923. (PMID: 28576882)
J Neurosci. 2018 Feb 14;38(7):1802-1820. (PMID: 29335358)
J Neurosci. 2015 Aug 19;35(33):11482-99. (PMID: 26290228)
PLoS One. 2015 Dec 28;10(12):e0145334. (PMID: 26709696)
Nature. 2012 Sep 6;489(7414):91-100. (PMID: 22955619)
J Neurosci Res. 2006 Aug 15;84(3):534-41. (PMID: 16773649)
J Neurosci. 2022 Nov 9;42(45):8542-8555. (PMID: 36198499)
FEBS Lett. 2008 Apr 9;582(8):1237-44. (PMID: 18275855)
Cold Spring Harb Perspect Biol. 2015 Jul 01;7(9):a020461. (PMID: 26134004)
Cell. 2024 Oct 3;187(20):5753-5774.e28. (PMID: 39265576)
Development. 2001 Jul;128(14):2723-33. (PMID: 11526078)
Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658)
Nat Genet. 2013 Jun;45(6):580-5. (PMID: 23715323)
Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2243-E2252. (PMID: 28246330)
Cell Host Microbe. 2015 Dec 9;18(6):714-22. (PMID: 26651947)
Nucleic Acids Res. 2020 Feb 20;48(3):1254-1270. (PMID: 31828317)
BMC Genomics. 2009 Jan 14;10:22. (PMID: 19144180)
Nat Commun. 2016 Mar 09;7:10883. (PMID: 26955760)
Brief Bioinform. 2024 Mar 27;25(3):. (PMID: 38653489)
PLoS Comput Biol. 2015 Apr 17;11(4):e1004132. (PMID: 25884877)
Genome Res. 2002 Jun;12(6):996-1006. (PMID: 12045153)
PLoS Genet. 2019 May 2;15(5):e1008130. (PMID: 31048900)
Nat Neurosci. 2009 Nov;12(11):1398-406. (PMID: 19838178)
Nat Neurosci. 2022 Aug;25(8):1104-1112. (PMID: 35915177)
Sci Rep. 2017 Oct 26;7(1):14133. (PMID: 29074959)
Mol Plant. 2022 Nov 7;15(11):1807-1824. (PMID: 36307979)
Nucleic Acids Res. 2012 Oct;40(18):8849-61. (PMID: 22798495)
Nat Commun. 2021 Aug 6;12(1):4763. (PMID: 34362918)
Int J Dev Neurosci. 2018 Nov;70:3-11. (PMID: 29964158)
Commun Biol. 2022 Nov 12;5(1):1238. (PMID: 36371468)
J Neurosci. 2004 Dec 15;24(50):11215-25. (PMID: 15601927)
Bioinformatics. 2010 May 15;26(10):1378-80. (PMID: 20378558)
Inflamm Regen. 2022 Mar 2;42(1):7. (PMID: 35232486)
Genes Dev. 2010 Feb 1;24(3):301-11. (PMID: 20080941)
Front Neurol. 2020 Feb 14;11:32. (PMID: 32117005)
World J Psychiatry. 2022 Feb 19;12(2):264-285. (PMID: 35317338)
Nat Struct Mol Biol. 2016 Apr;23(4):349-57. (PMID: 26926434)
Nucleic Acids Res. 2022 Jan 7;50(D1):D165-D173. (PMID: 34850907)
Nat Commun. 2020 Jan 8;11(1):124. (PMID: 31913281)
Genome Med. 2021 May 27;13(1):95. (PMID: 34044854)
Cell Rep. 2018 May 22;23(8):2254-2263. (PMID: 29791837)
Biomolecules. 2021 Nov 03;11(11):. (PMID: 34827627)
Sci Adv. 2023 Oct 13;9(41):eadg3754. (PMID: 37824614)
Nat Commun. 2018 Mar 2;9(1):899. (PMID: 29500351)
Nat Biotechnol. 2015 May;33(5):495-502. (PMID: 25867923)

RF1MH128695 U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH); 2144475 NSF | BIO | Division of Biological Infrastructure (DBI); R21 NS128761 United States NS NINDS NIH HHS; P50 HD105353 United States HD NICHD NIH HHS; R01 AG067025 United States AG NIA NIH HHS; R21NS128761 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); RF1 MH128695 United States MH NIMH NIH HHS; R21NS127432 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

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Date Created: 20250205 Date Completed: 20250205 Latest Revision: 20250208

20250208

PMC11799153

10.1038/s42003-025-07570-6

39910206