Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2

Yasunari Yamanaka, Mohammad A Faghihi, Marco Magistri, Oscar Alvarez-Garcia, Martin Lotz, Claes R Wahlestedt

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 (. Lrp1), referred to as Lrp1-AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity ofHmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein and increase Lrp1 expression by enhancing Hmgb2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.

Original languageEnglish (US)
Pages (from-to)967-976
Number of pages10
JournalCell Reports
Volume11
Issue number6
DOIs
StatePublished - May 12 2015

Fingerprint

HMGB2 Protein
Long Noncoding RNA
Low Density Lipoprotein Receptor-Related Protein-1
Antisense RNA
Transcription
Gene expression
Oligonucleotides
Chromatin
Brain
Alzheimer Disease
Up-Regulation
Down-Regulation
Tissue
Gene Expression
Polymerase Chain Reaction
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2. / Yamanaka, Yasunari; Faghihi, Mohammad A; Magistri, Marco; Alvarez-Garcia, Oscar; Lotz, Martin; Wahlestedt, Claes R.

In: Cell Reports, Vol. 11, No. 6, 12.05.2015, p. 967-976.

Research output: Contribution to journalArticle

Yamanaka, Yasunari ; Faghihi, Mohammad A ; Magistri, Marco ; Alvarez-Garcia, Oscar ; Lotz, Martin ; Wahlestedt, Claes R. / Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2. In: Cell Reports. 2015 ; Vol. 11, No. 6. pp. 967-976.
@article{2da4397bfedf42ef8164b97a9ae87b38,
title = "Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2",
abstract = "Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 (. Lrp1), referred to as Lrp1-AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity ofHmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein and increase Lrp1 expression by enhancing Hmgb2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.",
author = "Yasunari Yamanaka and Faghihi, {Mohammad A} and Marco Magistri and Oscar Alvarez-Garcia and Martin Lotz and Wahlestedt, {Claes R}",
year = "2015",
month = "5",
day = "12",
doi = "10.1016/j.celrep.2015.04.011",
language = "English (US)",
volume = "11",
pages = "967--976",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2

AU - Yamanaka, Yasunari

AU - Faghihi, Mohammad A

AU - Magistri, Marco

AU - Alvarez-Garcia, Oscar

AU - Lotz, Martin

AU - Wahlestedt, Claes R

PY - 2015/5/12

Y1 - 2015/5/12

N2 - Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 (. Lrp1), referred to as Lrp1-AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity ofHmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein and increase Lrp1 expression by enhancing Hmgb2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.

AB - Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 (. Lrp1), referred to as Lrp1-AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity ofHmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein and increase Lrp1 expression by enhancing Hmgb2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.

UR - http://www.scopus.com/inward/record.url?scp=84929267287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929267287&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.04.011

DO - 10.1016/j.celrep.2015.04.011

M3 - Article

C2 - 25937287

AN - SCOPUS:84929267287

VL - 11

SP - 967

EP - 976

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 6

ER -