Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain

W. Mandemakers; L. Abuhatzira; H. Xu; L. A. Caromile; S. S. Hébert; A. Snellinx; V. A. Morais; S. Matta; T. Cai; A. L. Notkins; B. De Strooper

doi:10.1007/s00125-013-2901-5

Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain

W. Mandemakers, L. Abuhatzira, H. Xu, L. A. Caromile, S. S. Hébert, A. Snellinx, V. A. Morais, S. Matta, T. Cai, A. L. Notkins, B. De Strooper^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Aims/hypothesis:

We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2β. We also identified miR-153 target genes that correlated with IA-2β localisation and function.

Methods:

A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2β, quantitative PCR analysis of miR-153 and Ia-2β (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2β single knockout and Ia-2/Ia-2β double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out.

Results:

Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2β, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2β in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2β knockout and Ia-2/Ia-2β double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2β expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels.

Conclusions/ interpretation:

This study suggests the involvement of miR-153, IA-2β and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release.

Original language	English
Pages (from-to)	1547-1556
Number of pages	10
Journal	Diabetologia
Volume	56
Issue number	7
DOIs	https://doi.org/10.1007/s00125-013-2901-5
Publication status	Published - 18 Apr 2013
Externally published	Yes

Bibliographical note

Funding:
This work was supported, in part, by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, a Marie Curie Intra-European Fellowship (EIF proposal number 041333) awarded to W. Mandemakers, and a Methusalem grant (Flemish community and University of Leuven, Belgium) and European Research Commission (ERC) grant (EU Commission) to B. De Strooper.

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Mandemakers, W., Abuhatzira, L., Xu, H., Caromile, L. A., Hébert, S. S., Snellinx, A., Morais, V. A., Matta, S., Cai, T., Notkins, A. L., & De Strooper, B. (2013). Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain. Diabetologia, 56(7), 1547-1556. https://doi.org/10.1007/s00125-013-2901-5

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title = "Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain",

abstract = "Aims/hypothesis: We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2β. We also identified miR-153 target genes that correlated with IA-2β localisation and function. Methods: A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2β, quantitative PCR analysis of miR-153 and Ia-2β (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2β single knockout and Ia-2/Ia-2β double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Results:Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2β, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2β in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2β knockout and Ia-2/Ia-2β double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2β expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels.Conclusions/ interpretation: This study suggests the involvement of miR-153, IA-2β and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release.",

author = "W. Mandemakers and L. Abuhatzira and H. Xu and Caromile, {L. A.} and H{\'e}bert, {S. S.} and A. Snellinx and Morais, {V. A.} and S. Matta and T. Cai and Notkins, {A. L.} and {De Strooper}, B.",

note = "Funding: This work was supported, in part, by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, a Marie Curie Intra-European Fellowship (EIF proposal number 041333) awarded to W. Mandemakers, and a Methusalem grant (Flemish community and University of Leuven, Belgium) and European Research Commission (ERC) grant (EU Commission) to B. De Strooper.",

year = "2013",

month = apr,

day = "18",

doi = "10.1007/s00125-013-2901-5",

language = "English",

volume = "56",

pages = "1547--1556",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Science+Business Media",

number = "7",

}

Mandemakers, W, Abuhatzira, L, Xu, H, Caromile, LA, Hébert, SS, Snellinx, A, Morais, VA, Matta, S, Cai, T, Notkins, AL & De Strooper, B 2013, 'Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain', Diabetologia, vol. 56, no. 7, pp. 1547-1556. https://doi.org/10.1007/s00125-013-2901-5

TY - JOUR

T1 - Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β

T2 - identification of miR-153 target genes with functions related to IA-2β in pancreas and brain

AU - Mandemakers, W.

AU - Abuhatzira, L.

AU - Xu, H.

AU - Caromile, L. A.

AU - Hébert, S. S.

AU - Snellinx, A.

AU - Morais, V. A.

AU - Matta, S.

AU - Cai, T.

AU - Notkins, A. L.

AU - De Strooper, B.

N1 - Funding: This work was supported, in part, by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, a Marie Curie Intra-European Fellowship (EIF proposal number 041333) awarded to W. Mandemakers, and a Methusalem grant (Flemish community and University of Leuven, Belgium) and European Research Commission (ERC) grant (EU Commission) to B. De Strooper.

PY - 2013/4/18

Y1 - 2013/4/18

N2 - Aims/hypothesis: We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2β. We also identified miR-153 target genes that correlated with IA-2β localisation and function. Methods: A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2β, quantitative PCR analysis of miR-153 and Ia-2β (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2β single knockout and Ia-2/Ia-2β double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Results:Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2β, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2β in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2β knockout and Ia-2/Ia-2β double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2β expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels.Conclusions/ interpretation: This study suggests the involvement of miR-153, IA-2β and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release.

AB - Aims/hypothesis: We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2β. We also identified miR-153 target genes that correlated with IA-2β localisation and function. Methods: A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2β, quantitative PCR analysis of miR-153 and Ia-2β (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2β single knockout and Ia-2/Ia-2β double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Results:Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2β, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2β in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2β knockout and Ia-2/Ia-2β double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2β expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels.Conclusions/ interpretation: This study suggests the involvement of miR-153, IA-2β and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release.

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U2 - 10.1007/s00125-013-2901-5

DO - 10.1007/s00125-013-2901-5

M3 - Article

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AN - SCOPUS:84878828559

SN - 0012-186X

VL - 56

SP - 1547

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JO - Diabetologia

JF - Diabetologia

IS - 7

ER -

Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain

Abstract

Bibliographical note

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