DNMT1 regulates expression of MHC class I in post-mitotic neurons
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DNMT1 regulates expression of MHC class I in post-mitotic neurons. / Gustafsson, Julie Ry; Katsioudi, Georgia; Degn, Matilda; Ejlerskov, Patrick; Issazadeh-Navikas, Shohreh; Kornum, Birgitte Rahbek.
In: Molecular Brain, Vol. 11, No. 1, 36, 2018, p. 1-16.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - DNMT1 regulates expression of MHC class I in post-mitotic neurons
AU - Gustafsson, Julie Ry
AU - Katsioudi, Georgia
AU - Degn, Matilda
AU - Ejlerskov, Patrick
AU - Issazadeh-Navikas, Shohreh
AU - Kornum, Birgitte Rahbek
PY - 2018
Y1 - 2018
N2 - Major Histocompability Complex I (MHC-I) molecules present cellularly derived peptides to the adaptive immune system. Generally MHC-I is not expressed on healthy post-mitotic neurons in the central nervous system, but it is known to increase upon immune activation such as viral infections and also during neurodegenerative processes. MHC-I expression is known to be regulated by the DNA methyltransferase DNMT1 in non-neuronal cells. Interestingly DNMT1 expression is high in neurons despite these being non-dividing. This suggests a role for DNMT1 in neurons beyond the classical re-methylation of DNA after cell division. We thus investigated whether DNMT1 regulates MHC-I in post-mitotic neurons. For this we used primary cultures of mouse cerebellar granule neurons (CGNs). Our results showed that knockdown of DNMT1 in CGNs caused upregulation of some, but not all subtypes of MHC-I genes. This effect was synergistically enhanced by subsequent IFNγ treatment. Overall MHC-I protein level was not affected by knockdown of DNMT1 in CGNs. Instead our results show that the relative MHC-I expression levels among the different MHC subtypes is regulated by DNMT1 activity. In conclusion, we show that while the mouse H2-D1/L alleles are suppressed in neurons by DNMT1 activity under normal circumstances, the H2-K1 allele is not. This finding is particularly important in two instances. One: in the context of CNS autoimmunity with epitope presentation by specific MHC-I subtypes where this allele specific regulation might become important; and two: in amyotropic lateral sclerosis (ALS) where H2-K but not H2-D protects motor neurons from ALS astrocyte-induced toxicity in a mouse model of ALS.
AB - Major Histocompability Complex I (MHC-I) molecules present cellularly derived peptides to the adaptive immune system. Generally MHC-I is not expressed on healthy post-mitotic neurons in the central nervous system, but it is known to increase upon immune activation such as viral infections and also during neurodegenerative processes. MHC-I expression is known to be regulated by the DNA methyltransferase DNMT1 in non-neuronal cells. Interestingly DNMT1 expression is high in neurons despite these being non-dividing. This suggests a role for DNMT1 in neurons beyond the classical re-methylation of DNA after cell division. We thus investigated whether DNMT1 regulates MHC-I in post-mitotic neurons. For this we used primary cultures of mouse cerebellar granule neurons (CGNs). Our results showed that knockdown of DNMT1 in CGNs caused upregulation of some, but not all subtypes of MHC-I genes. This effect was synergistically enhanced by subsequent IFNγ treatment. Overall MHC-I protein level was not affected by knockdown of DNMT1 in CGNs. Instead our results show that the relative MHC-I expression levels among the different MHC subtypes is regulated by DNMT1 activity. In conclusion, we show that while the mouse H2-D1/L alleles are suppressed in neurons by DNMT1 activity under normal circumstances, the H2-K1 allele is not. This finding is particularly important in two instances. One: in the context of CNS autoimmunity with epitope presentation by specific MHC-I subtypes where this allele specific regulation might become important; and two: in amyotropic lateral sclerosis (ALS) where H2-K but not H2-D protects motor neurons from ALS astrocyte-induced toxicity in a mouse model of ALS.
KW - Autoimmune neurodegeneration
KW - DNMT1
KW - H2
KW - HLA
KW - MHC class I
KW - Post mitotic neurons
U2 - 10.1186/s13041-018-0380-9
DO - 10.1186/s13041-018-0380-9
M3 - Journal article
C2 - 29970123
AN - SCOPUS:85049472048
VL - 11
SP - 1
EP - 16
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 36
ER -
ID: 211861810