BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.
Androstenes
/ pharmacology
Anticholesteremic Agents
/ pharmacology
Azepines
/ pharmacology
Cell Cycle Proteins
/ genetics
Cholesterol
/ metabolism
Epithelial Cells
/ drug effects
Gene Expression Regulation
Gene Silencing
HEK293 Cells
Humans
Nuclear Proteins
/ genetics
Receptors, sigma
/ metabolism
Retinal Pigment Epithelium
/ cytology
Signal Transduction
/ drug effects
Sterol Regulatory Element Binding Protein 1
/ genetics
Sterol Regulatory Element Binding Protein 2
/ genetics
Transcription Factors
/ genetics
Transcription, Genetic
/ genetics
Transfection
Triazoles
/ pharmacology
Up-Regulation
/ genetics
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
04
09
2019
revised:
10
11
2020
accepted:
11
11
2020
entrez:
25
11
2020
pubmed:
26
11
2020
medline:
15
9
2021
Statut:
epublish
Résumé
The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation. Cholesterol deprivation was induced in ARPE19 cells using a blocker of lysosomal cholesterol export. This condition up-regulated S2R mRNA and protein, and also SREBP2 but not SREBP1, both transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD3 or BRD4 (though widely deemed a master regulator) averted S2R up-regulation that was induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, endogenous BRD2 co-immunoprecipitated with the transcription-active N-terminal half of SREBP2, and chromatin immunoprecipitation-qPCR signified co-occupancy of BRD2, H3K27ac (histone acetylation), and SREBP2Nterm at the S2R gene promoter. In summary, this study reveals a previously unrecognized BRD2/SREBP2 cooperative regulation of S2R transcription, thus shedding new light on signaling in response to cholesterol deprivation.
Identifiants
pubmed: 33234676
pii: 4/1/e201900540
doi: 10.26508/lsa.201900540
pmc: PMC7723276
pii:
doi:
Substances chimiques
(+)-JQ1 compound
0
Androstenes
0
Anticholesteremic Agents
0
Azepines
0
BRD2 protein, human
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Nuclear Proteins
0
Receptors, sigma
0
SREBF1 protein, human
0
SREBF2 protein, human
0
Sterol Regulatory Element Binding Protein 1
0
Sterol Regulatory Element Binding Protein 2
0
Transcription Factors
0
Triazoles
0
sigma-2 receptor
0
3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
3039-71-2
Cholesterol
97C5T2UQ7J
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
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL129785
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133665
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107239
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143469
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY029809
Pays : United States
Informations de copyright
© 2020 Shen et al.
Références
Mol Cell. 2017 May 18;66(4):517-532.e9
pubmed: 28525743
Science. 2018 Jul 27;361(6400):
pubmed: 29930091
Hum Mol Genet. 2016 Aug 15;25(16):3588-3599
pubmed: 27378690
J Am Coll Cardiol. 2010 Jun 8;55(23):2580-9
pubmed: 20513599
ACS Chem Neurosci. 2018 May 16;9(5):1014-1026
pubmed: 29426225
Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):
pubmed: 28213432
Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32
pubmed: 22509028
EBioMedicine. 2015 Sep 28;2(11):1650-61
pubmed: 26870791
Adv Pharmacol. 2014;69:323-86
pubmed: 24484982
Cell Metab. 2009 Jul;10(1):63-75
pubmed: 19583955
Mol Cell. 2014 Jun 5;54(5):728-36
pubmed: 24905006
Cell. 2012 Mar 30;149(1):214-31
pubmed: 22464331
Nature. 2020 Jul;583(7816):459-468
pubmed: 32353859
Cell. 2011 Sep 16;146(6):904-17
pubmed: 21889194
Front Genet. 2014 Dec 11;5:439
pubmed: 25566323
Elife. 2015 Dec 08;4:
pubmed: 26646182
Nat Commun. 2017 Dec 20;8(1):2217
pubmed: 29263365
J Pharmacol Exp Ther. 2015 Aug;354(2):203-12
pubmed: 26034081
J Leukoc Biol. 2016 Oct;100(4):679-686
pubmed: 27450555
J Leukoc Biol. 2018 Aug;104(2):265-274
pubmed: 29493812
Life Sci Alliance. 2020 Nov 24;4(1):
pubmed: 33234676
Yale J Biol Med. 2017 Mar 29;90(1):63-71
pubmed: 28356894
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2144-2149
pubmed: 29444854
Handb Exp Pharmacol. 2017;244:309-330
pubmed: 28176045
Neuropsychopharmacology. 2018 Aug;43(9):1867-1875
pubmed: 29728649
Cell. 1997 May 2;89(3):331-40
pubmed: 9150132
Cell. 2015 Apr 9;161(2):291-306
pubmed: 25860611
Invest Ophthalmol Vis Sci. 2018 Mar 20;59(4):AMD160-AMD181
pubmed: 30357336
Circ Res. 2020 Apr 24;126(9):1190-1208
pubmed: 32324495
Front Pharmacol. 2018 Jul 10;9:711
pubmed: 30042674
Trends Biochem Sci. 2015 Aug;40(8):468-79
pubmed: 26145250
Cell. 2013 Apr 11;153(2):307-19
pubmed: 23582322
ACS Chem Neurosci. 2017 Aug 16;8(8):1801-1811
pubmed: 28644012
Nature. 2010 Dec 23;468(7327):1119-23
pubmed: 21068722
Cell. 2017 Feb 9;168(4):629-643
pubmed: 28187285
Nat Commun. 2017 Nov 22;8(1):1707
pubmed: 29167426
Nat Struct Mol Biol. 2016 Jun;23(6):540-8
pubmed: 27159561
Clin Epigenetics. 2018 Mar 27;10:40
pubmed: 29599847
Mol Cell. 2014 Oct 23;56(2):219-231
pubmed: 25263595
Nat Rev Drug Discov. 2014 May;13(5):337-56
pubmed: 24751816
Front Pharmacol. 2018 Dec 06;9:1345
pubmed: 30574087
ACS Chem Neurosci. 2019 Mar 20;10(3):1595-1602
pubmed: 30421909
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165
pubmed: 28559337