Aging-Associated Changes in Cognition, Expression and Epigenetic Regulation of Chondroitin 6-Sulfotransferase Chst3 .

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Epigenesis, Genetic* ; Proteoglycans*; Aging/genetics ; Animals ; Cognition ; Mice ; RNA, Messenger ; Sulfotransferases ; Carbohydrate Sulfotransferases

Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related genes in the hippocampus of young, aged and very aged mice. ECM gene expression was downregulated, despite the accumulation of ECM proteoglycans during aging. The most robustly downregulated gene was carbohydrate sulfotransferase 3 ( Chst3 ), the enzyme responsible for the chondroitin 6-sulfation (C6S) of proteoglycans. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of the Chst3 gene, resulting in the downregulation of Chst3 expression in non-neuronal cells. Cluster analysis revealed that the expression of lecticans-substrates of CHST3-is tightly co-regulated with this enzyme. These changes in ECM-related genes were accompanied by an age-confounded decline in cognitive performance. Despite the co-directional impairment in cognitive function and average Chst3 expression in the studied age groups, at the individual level we found a negative correlation between mRNA levels of Chst3 and cognitive performance within the very aged group. An analysis of correlations between the expression of ECM-related genes and cognitive performance in novel object versus novel location recognition tasks revealed an apparent trade-off in the positive gene effects in one task at the expense of another. Further analysis revealed that, despite the reduction in the Chst3 mRNA, the expression of CHST3 protein is increased in glial cells but not in neurons, which, however, does not lead to changes in the absolute level of C6S and even results in the decrease in C6S in perineuronal, perisynaptic and periaxonal ECM relative to the elevated expression of its protein carrier versican.

Neuroscience. 2005;133(3):749-62. (PMID: 15896911)
Front Integr Neurosci. 2018 Feb 02;12:3. (PMID: 29456495)
J Neurosci Res. 2018 Apr;96(4):573-588. (PMID: 29344975)
Am J Hum Genet. 2013 Mar 7;92(3):366-74. (PMID: 23415669)
Am J Med Genet A. 2017 Jan;173(1):163-168. (PMID: 27753269)
J Neurochem. 2018 Oct;147(2):137-152. (PMID: 29873074)
Brain Res Bull. 2018 Jan;136:101-108. (PMID: 28284900)
Int J Cell Biol. 2015;2015:367579. (PMID: 26472958)
Biochim Biophys Acta. 2013 Oct;1830(10):4719-33. (PMID: 23774590)
Nat Rev Neurosci. 2003 Jun;4(6):456-68. (PMID: 12778118)
Biochim Biophys Acta Gen Subj. 2017 Oct;1861(10):2420-2434. (PMID: 28625420)
Nature. 2019 Apr;568(7751):187-192. (PMID: 30944478)
FASEB J. 2005 Aug;19(10):1329-31. (PMID: 15919760)
N Engl J Med. 2001 Feb 1;344(5):363-70. (PMID: 11172169)
Neuron. 2010 Oct 6;68(1):9-18. (PMID: 20920787)
J Biol Chem. 2006 Dec 15;281(50):38668-74. (PMID: 17040900)
Front Aging Neurosci. 2018 Dec 17;10:411. (PMID: 30631278)
Cell Rep. 2017 Jul 18;20(3):538-548. (PMID: 28723559)
Nature. 2011 Oct 26;478(7370):483-9. (PMID: 22031440)
Nat Rev Neurosci. 2006 Jan;7(1):30-40. (PMID: 16371948)
Curr Protoc Mouse Biol. 2015 Dec 02;5(4):291-309. (PMID: 26629773)
Chem Biol. 1999 Jan;6(1):R9-R22. (PMID: 9889154)
Brain Res Bull. 1999 Aug;49(6):377-91. (PMID: 10483914)
J Cell Sci. 1995 Mar;108 ( Pt 3):1307-15. (PMID: 7622613)
Nucleic Acids Res. 2019 Apr 23;47(7):3434-3449. (PMID: 30759223)
Can J Biochem Cell Biol. 1985 Apr;63(4):268-71. (PMID: 4016573)
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10155-60. (PMID: 15215498)
Front Cell Neurosci. 2014 Nov 27;8:396. (PMID: 25505873)
Mol Cell Proteomics. 2014 Nov;13(11):2975-85. (PMID: 25044018)
J Neurosci Methods. 2006 Sep 30;156(1-2):101-10. (PMID: 16554095)
J Neurosci. 2008 Jan 2;28(1):264-78. (PMID: 18171944)
IBRO Rep. 2016 Dec;1:54-60. (PMID: 28713865)
Nat Rev Mol Cell Biol. 2014 Dec;15(12):786-801. (PMID: 25415508)
J Clin Invest. 2013 Nov;123(11):4909-17. (PMID: 24216480)
Neuron Glia Biol. 2008 Aug;4(3):235-47. (PMID: 19497143)
FASEB J. 2020 Feb;34(2):2853-2868. (PMID: 31908019)
Curr Biol. 2007 Sep 4;17(17):R742-3. (PMID: 17803918)
Brain. 2010 Aug;133(Pt 8):2331-47. (PMID: 20566484)
Hum Brain Mapp. 2010 Jun;31(6):879-90. (PMID: 20496379)
Front Aging Neurosci. 2010 Jan 04;1:6. (PMID: 20552057)
J Leukoc Biol. 2001 Apr;69(4):565-74. (PMID: 11310842)
Int J Mol Sci. 2011;12(9):5461-70. (PMID: 22016602)
Nat Rev Genet. 2012 Mar 13;13(4):227-32. (PMID: 22411467)
Bioessays. 2017 Jan;39(1):1-12. (PMID: 28004446)
J Cell Sci. 2008 Sep 15;121(Pt 18):3083-91. (PMID: 18768934)
Neural Plast. 2016;2016:5214961. (PMID: 26881114)
Int J Mol Sci. 2019 Jan 22;20(3):. (PMID: 30678217)
Dev Neurobiol. 2007 Apr;67(5):570-88. (PMID: 17443809)
J Neurosci. 2004 Oct 20;24(42):9372-82. (PMID: 15496673)
J Neurochem. 2009 Sep;110(5):1547-56. (PMID: 19627440)
Aging (Albany NY). 2017 Jun 28;9(6):1607-1622. (PMID: 28657900)
Neural Plast. 2016;2016:4327082. (PMID: 26989516)
Cell Rep. 2019 Jan 8;26(2):381-393.e6. (PMID: 30625321)
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1896-E1905. (PMID: 29437957)
Respir Res. 2015 Dec 09;16:146. (PMID: 26646821)
Stem Cell Res Ther. 2018 Feb 05;9(1):28. (PMID: 29402304)
Nat Neurosci. 2012 Jan 15;15(3):414-22, S1-2. (PMID: 22246436)
Cells. 2021 Jul 22;10(8):. (PMID: 34440631)
FEBS J. 2019 May;286(10):1815-1837. (PMID: 30637950)
Neural Regen Res. 2019 Apr;14(4):578-581. (PMID: 30632493)
J Neurosci. 2017 Apr 26;37(17):4493-4507. (PMID: 28336567)
Cell Rep. 2018 Oct 16;25(3):640-650.e2. (PMID: 30332644)
Exp Neurol. 2014 Mar;253:197-207. (PMID: 24424280)
Nat Rev Neurosci. 2019 Aug;20(8):451-465. (PMID: 31263252)
Mol Psychiatry. 2021 Oct;26(10):5658-5668. (PMID: 34272488)
Stroke. 2001 May;32(5):1208-15. (PMID: 11340235)
Genome Biol. 2021 Jan 5;22(1):17. (PMID: 33402207)
Nat Neurosci. 2016 Jan;19(1):102-10. (PMID: 26656643)
Nature. 2018 Oct;562(7727):367-372. (PMID: 30283141)
Cogn Process. 2012 May;13(2):93-110. (PMID: 22160349)
J Histochem Cytochem. 2021 Jan;69(1):61-80. (PMID: 32936033)
Sci Rep. 2020 Oct 14;10(1):17308. (PMID: 33057053)
Curr Opin Struct Biol. 2003 Oct;13(5):612-20. (PMID: 14568617)
Elife. 2018 Oct 02;7:. (PMID: 30274593)
PLoS One. 2014 Mar 25;9(3):e92381. (PMID: 24667694)
Mol Neurobiol. 2017 Dec;54(10):8071-8089. (PMID: 27889895)
Nature. 2002 Sep 26;419(6905):407-11. (PMID: 12353038)
Neural Plast. 2016;2016:1305801. (PMID: 27057358)
Cereb Cortex. 2017 Feb 1;27(2):903-918. (PMID: 28119345)
Am J Hum Genet. 2008 Jun;82(6):1368-74. (PMID: 18513679)
Brain Pathol. 2009 Oct;19(4):573-85. (PMID: 18662234)
BMC Neurosci. 2008 Jan 25;9:14. (PMID: 18221525)

Keywords: 6-sulfation; aging; carbohydrate sulfotransferase 3; cognitive decline; epigenetic regulation; extracellular matrix

0 (Proteoglycans)
0 (RNA, Messenger)
EC 2.8.2.- (Sulfotransferases)

Date Created: 20220709 Date Completed: 20220712 Latest Revision: 20231213

20250114

PMC9266018

10.3390/cells11132033

35805117