Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis.
Autoimmune diseases
Autoimmunity
Cell Biology
Epigenetics
Fibrosis
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
09
12
2019
accepted:
17
06
2020
pubmed:
1
7
2020
medline:
9
2
2021
entrez:
1
7
2020
Statut:
ppublish
Résumé
TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis.
Identifiants
pubmed: 32603313
pii: 135439
doi: 10.1172/JCI135439
pmc: PMC7456219
doi:
pii:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DDIT4L protein, human
0
Ddit4l protein, mouse
0
RNA, Long Noncoding
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4888-4905Subventions
Organisme : NCATS NIH HHS
ID : KL2 TR003168
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK123704
Pays : United States
Références
Elife. 2013 Dec 31;2:e01749
pubmed: 24381249
Arthritis Rheum. 1996 Aug;39(8):1338-46
pubmed: 8702442
Ann Rheum Dis. 1994 Nov;53(11):763-7
pubmed: 7826139
Nat Rev Rheumatol. 2009 Apr;5(4):200-6
pubmed: 19337284
Arthritis Rheum. 2001 Jul;44(7):1667-76
pubmed: 11465719
Ann Rheum Dis. 2013 Nov;72(11):1747-55
pubmed: 24092682
Database (Oxford). 2017 Jan 1;2017:
pubmed: 28605766
J Cell Mol Med. 2019 Jul;23(7):4738-4745
pubmed: 31062436
Nucleic Acids Res. 2013 Feb 1;41(3):1450-63
pubmed: 23275551
EMBO Rep. 2012 Nov 6;13(11):971-83
pubmed: 23070366
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Arthritis Rheum. 2011 Jun;63(6):1707-17
pubmed: 21370225
Nat Rev Rheumatol. 2014 Dec;10(12):706-19
pubmed: 25136781
Nat Rev Nephrol. 2016 Jun;12(6):325-38
pubmed: 27108839
Circ Res. 2017 Aug 18;121(5):575-583
pubmed: 28630135
Nature. 2014 Jan 30;505(7485):635-40
pubmed: 24463510
J Clin Invest. 2007 Mar;117(3):557-67
pubmed: 17332883
Nucleic Acids Res. 2019 Jul 2;47(W1):W158-W165
pubmed: 31165883
FEBS J. 2016 Jun;283(12):2219-32
pubmed: 26807763
J Biol Chem. 2001 Jun 8;276(23):19945-53
pubmed: 11262418
Sci Transl Med. 2017 Dec 13;9(420):
pubmed: 29237758
Nat Rev Dis Primers. 2015 Apr 23;1:15002
pubmed: 27189141
Sci Rep. 2017 Feb 15;7:42657
pubmed: 28198439
Radiother Oncol. 2014 May;111(2):186-93
pubmed: 24835153
Biochemistry. 1975 Nov 18;14(23):5194-9
pubmed: 43
Cell Death Differ. 2015 Apr;22(4):612-25
pubmed: 25257176
Nat Commun. 2015 Jul 24;6:7743
pubmed: 26205790
Mol Biol Cell. 2003 Jun;14(6):2508-19
pubmed: 12808047
J Cell Physiol. 2004 Mar;198(3):350-8
pubmed: 14755540
Genome Biol. 2018 Oct 4;19(1):151
pubmed: 30286773
J Am Coll Cardiol. 2015 Nov 3;66(18):2005-2015
pubmed: 26516004
Arthritis Rheum. 2011 Mar;63(3):783-94
pubmed: 21360508
Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55
pubmed: 24316576
Can J Gastroenterol. 2005 Sep;19 Suppl A:5A-36A
pubmed: 16151544
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Ann Intern Med. 2010 Feb 2;152(3):159-66
pubmed: 20124232
Sci Signal. 2017 Feb 28;10(468):
pubmed: 28246202
Nat Struct Mol Biol. 2014 Feb;21(2):198-206
pubmed: 24463464
Oncotarget. 2016 Aug 9;7(32):51473-51481
pubmed: 27391349
Curr Opin Rheumatol. 2014 Mar;26(2):131-7
pubmed: 24441644
Mol Cell. 2011 Nov 18;44(4):667-78
pubmed: 21963238
Arthritis Rheumatol. 2015 Nov;67(11):3016-26
pubmed: 26238292
Nat Cell Biol. 2012 Jun 10;14(7):659-65
pubmed: 22684254
J Cell Biochem. 2019 Jun;120(6):10821-10829
pubmed: 30672010
Cell. 2018 Jan 25;172(3):393-407
pubmed: 29373828
Wound Repair Regen. 2016 Mar;24(2):215-22
pubmed: 26704519
Nature. 2001 Feb 15;409(6822):860-921
pubmed: 11237011
Nat Med. 2015 Feb;21(2):150-8
pubmed: 25581517
Cell. 2014 Mar 27;157(1):77-94
pubmed: 24679528
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
Theranostics. 2018 Apr 15;8(10):2814-2829
pubmed: 29774077
J Vis Exp. 2012 Mar 25;(61):
pubmed: 22472705
Int J Burns Trauma. 2012;2(1):18-28
pubmed: 22928164
Biochim Biophys Acta. 2014 Nov;1842(11):2204-15
pubmed: 25201080
Arthritis Rheumatol. 2014 Mar;66(3):714-25
pubmed: 24574232
Int J Dev Biol. 2000 Apr;44(3):253-65
pubmed: 10853822
Nat Struct Mol Biol. 2017 Mar 3;24(3):197-204
pubmed: 28257137
Int J Mol Sci. 2018 Aug 20;19(8):
pubmed: 30127261