JMJD3 Intrinsically Disordered Region Links the 3D-genome Structure to TGFβ-dependent Transcription Activation

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jun 7

PMID 35672304

Authors

Marta Vicioso-Mantis

Raquel Fueyo

Claudia Navarro

Sara Cruz-Molina

Wilfred F J van IJcken

Elena Rebollo

Alvaro Rada-Iglesias

Marian A Martinez-Balbas

Affiliations

Soon will be listed here.

Abstract

Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFβ-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFβ pathway drives the assembly of an enhancer-cluster and precise gene activation. We discover that the TGFβ pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrate that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer-cluster. Overall, in this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFβ-driven response during mammalian neurogenesis.

Citing Articles

Liquid condensates: a new barrier to loop extrusion?.

Selivanovskiy A, Molodova M, Khrameeva E, Ulianov S, Razin S Cell Mol Life Sci. 2025; 82(1):80.

PMID: 39976773 PMC: 11842697. DOI: 10.1007/s00018-024-05559-8.

Transcription regulation by biomolecular condensates.

Pei G, Lyons H, Li P, Sabari B Nat Rev Mol Cell Biol. 2024; 26(3):213-236.

PMID: 39516712 DOI: 10.1038/s41580-024-00789-x.

Epigenetics and environmental health.

Zhang M, Hu T, Ma T, Huang W, Wang Y Front Med. 2024; 18(4):571-596.

PMID: 38806988 DOI: 10.1007/s11684-023-1038-2.

Super-enhancers: drivers of cells' identities and cells' debacles.

Lavaud M, Tesfaye R, Lassous L, Brounais B, Baudhuin M, Verrecchia F Epigenomics. 2024; .

PMID: 38587919 PMC: 11160454. DOI: 10.2217/epi-2023-0409.

Dynamic microenvironments shape nuclear organization and gene expression.

Hayward-Lara G, Fischer M, Mir M Curr Opin Genet Dev. 2024; 86:102177.

PMID: 38461773 PMC: 11162947. DOI: 10.1016/j.gde.2024.102177.

References

Dunker A, Bondos S, Huang F, Oldfield C . Intrinsically disordered proteins and multicellular organisms. Semin Cell Dev Biol. 2014; 37:44-55. DOI: 10.1016/j.semcdb.2014.09.025. View

Roussa E, Wiehle M, Dunker N, Becker-Katins S, Oehlke O, Krieglstein K . Transforming growth factor beta is required for differentiation of mouse mesencephalic progenitors into dopaminergic neurons in vitro and in vivo: ectopic induction in dorsal mesencephalon. Stem Cells. 2006; 24(9):2120-9. DOI: 10.1634/stemcells.2005-0514. View

Asensio-Juan E, Fueyo R, Pappa S, Iacobucci S, Badosa C, Lois S . The histone demethylase PHF8 is a molecular safeguard of the IFNγ response. Nucleic Acids Res. 2017; 45(7):3800-3811. PMC: 5397186. DOI: 10.1093/nar/gkw1346. View

Phillips-Cremins J, Sauria M, Sanyal A, Gerasimova T, Lajoie B, Bell J . Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell. 2013; 153(6):1281-95. PMC: 3712340. DOI: 10.1016/j.cell.2013.04.053. View

Bolognesi B, Gotor N, Dhar R, Cirillo D, Baldrighi M, Tartaglia G . A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression. Cell Rep. 2016; 16(1):222-231. PMC: 4929146. DOI: 10.1016/j.celrep.2016.05.076. View

Cramer P . Organization and regulation of gene transcription. Nature. 2019; 573(7772):45-54. DOI: 10.1038/s41586-019-1517-4. View

Mir M, Bickmore W, Furlong E, Narlikar G . Chromatin topology, condensates and gene regulation: shifting paradigms or just a phase?. Development. 2019; 146(19). PMC: 6803379. DOI: 10.1242/dev.182766. View

Hansen A, Cattoglio C, Darzacq X, Tjian R . Recent evidence that TADs and chromatin loops are dynamic structures. Nucleus. 2017; 9(1):20-32. PMC: 5990973. DOI: 10.1080/19491034.2017.1389365. View

Fuxreiter M . Fuzziness in Protein Interactions-A Historical Perspective. J Mol Biol. 2018; 430(16):2278-2287. DOI: 10.1016/j.jmb.2018.02.015. View

10.

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

11.

Phair R, Misteli T . High mobility of proteins in the mammalian cell nucleus. Nature. 2000; 404(6778):604-9. DOI: 10.1038/35007077. View

12.

Agger K, Cloos P, Christensen J, Pasini D, Rose S, Rappsilber J . UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007; 449(7163):731-4. DOI: 10.1038/nature06145. View

13.

Krijger P, Geeven G, Bianchi V, Hilvering C, de Laat W . 4C-seq from beginning to end: A detailed protocol for sample preparation and data analysis. Methods. 2019; 170:17-32. DOI: 10.1016/j.ymeth.2019.07.014. View

14.

Guo Y, Manteiga J, Henninger J, Sabari B, DallAgnese A, Hannett N . Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature. 2019; 572(7770):543-548. PMC: 6706314. DOI: 10.1038/s41586-019-1464-0. View

15.

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

16.

Davidson I, Bauer B, Goetz D, Tang W, Wutz G, Peters J . DNA loop extrusion by human cohesin. Science. 2019; 366(6471):1338-1345. DOI: 10.1126/science.aaz3418. View

17.

Nott T, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A . Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell. 2015; 57(5):936-947. PMC: 4352761. DOI: 10.1016/j.molcel.2015.01.013. View

18.

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

19.

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

20.

Kempfer R, Pombo A . Methods for mapping 3D chromosome architecture. Nat Rev Genet. 2019; 21(4):207-226. DOI: 10.1038/s41576-019-0195-2. View