Methyl-CpG binding domain 2 (Mbd2) is an epigenetic regulator of autism-risk genes and cognition.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
13 Jul 2023
13 Jul 2023
Historique:
received:
13
04
2023
accepted:
04
07
2023
revised:
29
06
2023
medline:
17
7
2023
pubmed:
14
7
2023
entrez:
13
7
2023
Statut:
epublish
Résumé
The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, downregulated genes are significantly enriched for human ortholog ASD risk genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2-/- mice. These findings suggest that Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.
Identifiants
pubmed: 37443311
doi: 10.1038/s41398-023-02561-9
pii: 10.1038/s41398-023-02561-9
pmc: PMC10344909
doi:
Substances chimiques
DNA-Binding Proteins
0
DNA
9007-49-2
Mbd2 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
259Informations de copyright
© 2023. The Author(s).
Références
J Neurosci. 2013 Mar 20;33(12):5275-84
pubmed: 23516292
JAMA. 2011 Nov 9;306(18):2001-10
pubmed: 22068992
Nat Commun. 2014 Nov 25;5:5601
pubmed: 25420914
Biochem Soc Trans. 2005 Dec;33(Pt 6):1537-40
pubmed: 16246164
J Neurosci. 2012 Jun 13;32(24):8219-30
pubmed: 22699903
EMBO Mol Med. 2014 Jul 07;6(8):1003-15
pubmed: 25001218
Nucleic Acids Res. 2017 Mar 17;45(5):2438-2457
pubmed: 27923996
Science. 2008 May 30;320(5880):1224-9
pubmed: 18511691
Neuron. 2015 Jul 1;87(1):231-43
pubmed: 26139376
Nat Genet. 2019 Jan;51(1):106-116
pubmed: 30559488
Genome Med. 2018 Mar 28;10(1):19
pubmed: 29587883
Glia. 2015 Jun;63(6):987-1004
pubmed: 25731131
Philos Trans R Soc Lond B Biol Sci. 2014 Sep 26;369(1652):
pubmed: 25135974
Nat Rev Mol Cell Biol. 2015 Mar;16(3):167-77
pubmed: 25693130
Psychiatr Genet. 2014 Oct;24(5):221-4
pubmed: 24849540
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
pubmed: 21106759
Biol Psychiatry. 2017 Feb 1;81(3):265-276
pubmed: 27769567
Brain Dev. 2005 Aug;27(5):321-5
pubmed: 15967618
J Neurochem. 2016 Oct;139 Suppl 2:179-199
pubmed: 26875778
Epigenomics. 2016 Apr;8(4):455-73
pubmed: 27066839
Cell. 1997 Feb 21;88(4):471-81
pubmed: 9038338
Nat Commun. 2012;3:1292
pubmed: 23250422
Science. 2017 May 5;356(6337):
pubmed: 28473536
Carcinogenesis. 2013 Dec;34(12):2738-49
pubmed: 23955541
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Biol Chem. 2002 Sep 27;277(39):35791-4
pubmed: 12177048
Front Neurosci. 2016 Jul 12;10:329
pubmed: 27462204
Ment Retard Dev Disabil Res Rev. 2002;8(2):87-93
pubmed: 12112733
J Neurosci. 2014 Jun 18;34(25):8630-45
pubmed: 24948817
Cell. 2013 Apr 11;153(2):480-92
pubmed: 23582333
Schizophr Res. 2015 Sep;167(1-3):35-41
pubmed: 25476119
Autism Res. 2012 Dec;5(6):385-97
pubmed: 23055267
Novartis Found Symp. 1998;214:6-16; discussion 16-21, 46-50
pubmed: 9601009
Front Cell Neurosci. 2017 Nov 20;11:359
pubmed: 29209173
Nucleic Acids Res. 2015 Mar 31;43(6):3046-55
pubmed: 25753672
Curr Opin Genet Dev. 2006 Jun;16(3):276-81
pubmed: 16647848
Neuron. 2016 Aug 17;91(4):739-747
pubmed: 27499081
J Neurosci. 2017 Jan 18;37(3):523-536
pubmed: 28100736
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3573-8
pubmed: 23401542
Pain. 2020 Oct;161(10):2394-2409
pubmed: 32427748
Cell. 2013 Feb 28;152(5):1146-59
pubmed: 23434322
Front Genet. 2016 Jun 21;7:115
pubmed: 27446199
Nat Genet. 1999 Oct;23(2):185-8
pubmed: 10508514
Behav Brain Res. 2006 Mar 15;168(1):172-5
pubmed: 16343653
Science. 2018 Feb 9;359(6376):693-697
pubmed: 29439242
Nucleic Acids Res. 2012 Sep 1;40(17):8255-65
pubmed: 22730288
Cancer Res. 2006 Sep 15;66(18):9202-10
pubmed: 16982764
Genome Res. 2021 Oct 19;:
pubmed: 34667120
Nat Rev Neurosci. 2016 Jul;17(7):411-23
pubmed: 27150399
Nucleic Acids Res. 2016 May 19;44(9):4037-51
pubmed: 27095194
Synapse. 2014 Oct;68(10):468-73
pubmed: 24985713
Mol Cell Biol. 1998 Nov;18(11):6538-47
pubmed: 9774669
Nucleic Acids Res. 2006 Jan 12;34(1):364-72
pubmed: 16410616
Hum Mol Genet. 2019 Jul 1;28(13):2201-2211
pubmed: 31220268
Genes Dev. 2001 Mar 15;15(6):710-23
pubmed: 11274056
Neuron. 2015 Sep 23;87(6):1215-1233
pubmed: 26402605
Mol Cell Biol. 2000 Jul;20(14):5107-18
pubmed: 10866667
Transl Psychiatry. 2018 Jul 2;8(1):125
pubmed: 29967385
Nature. 2009 May 7;459(7243):108-12
pubmed: 19295514
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6777-82
pubmed: 12748381
Cell Res. 2005 Apr;15(4):255-61
pubmed: 15857580
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nature. 2015 Feb 19;518(7539):365-9
pubmed: 25693568
Nucleic Acids Res. 2016 May 5;44(8):3549-66
pubmed: 26681691
Neurobiol Learn Mem. 2012 Jul;98(1):25-32
pubmed: 22542746
Transl Psychiatry. 2019 Jan 17;9(1):23
pubmed: 30655507
Science. 2007 Feb 23;315(5815):1143-7
pubmed: 17289941
Nat Genet. 1999 Sep;23(1):58-61
pubmed: 10471499
Cell. 1981 Nov;27(1 Pt 2):45-55
pubmed: 6276024
Mol Psychiatry. 2014 Aug;19(8):862-71
pubmed: 23999529
Nat Commun. 2020 Sep 25;11(1):4873
pubmed: 32978376
Elife. 2016 Nov 16;5:
pubmed: 27849519
Nucleic Acids Res. 1990 Jul 11;18(13):3975-82
pubmed: 1695733
Behav Neurosci. 2008 Apr;122(2):293-300
pubmed: 18410169
J Neurosci. 2016 Jan 27;36(4):1324-35
pubmed: 26818519
J Neurosci. 2006 Jan 4;26(1):319-27
pubmed: 16399702
Science. 2018 Dec 14;362(6420):
pubmed: 30545856
J Biochem. 2007 May;141(5):601-8
pubmed: 17405796
Carcinogenesis. 2014 Nov;35(11):2436-46
pubmed: 25178277
Mol Cell Biol. 2013 Oct;33(20):4106-15
pubmed: 23979593
Epigenomics. 2015;7(6):1051-73
pubmed: 25927341
Cereb Cortex. 2017 Dec 1;27(12):5739-5754
pubmed: 29028941
Brain Res. 2013 Aug 14;1526:15-25
pubmed: 23806776
Psychiatry Res. 2006 Nov 22;148(1):11-21
pubmed: 17056234
Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):E2807-16
pubmed: 24958888