Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression

Hdl Handle:
http://hdl.handle.net/10034/604083
Title:
Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression
Authors:
Wright, Paul W.; Li, Honchuan; Huehn, Andrew; O'Connor, Geraldine M.; Cooley, Sarah; Miller, Jeffrey S.; Anderson, Stephen K.
Abstract:
Members of the human KIR (killer cell immunoglobulin-like receptor) class I major histocompatibility complex receptor gene family contain multiple promoters that determine the variegated expression of KIR on natural killer cells. In order to identify novel genetic alterations associated with decreased KIR expression, a group of donors was characterized for KIR gene content, transcripts and protein expression. An individual with a single copy of the KIR2DL1 gene but a very low level of gene expression was identified. The low expression phenotype was associated with a single-nucleotide polymorphism (SNP) that created a binding site for the inhibitory ZEB1 (Zinc finger E-box-binding homeobox 1) transcription factor adjacent to a c-Myc binding site previously implicated in distal promoter activity. Individuals possessing this SNP had a substantial decrease in distal KIR2DL1 transcripts initiating from a novel intermediate promoter located 230 bp upstream of the proximal promoter start site. Surprisingly, there was no decrease in transcription from the KIR2DL1 proximal promoter. Reduced intermediate promoter activity revealed the existence of alternatively spliced KIR2DL1 transcripts containing premature termination codons that initiated from the proximal KIR2DL1 promoter. Altogether, these results indicate that distal transcripts are necessary for KIR2DL1 protein expression and are required for proper processing of sense transcripts from the bidirectional proximal promoter.
Affiliation:
Basic Science Program, Leidos Biomedical Research Inc., Lab of Experimental Immunology, Frederick National Lab, Frederick, MD, USA. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
Citation:
Wright, P. W., Li, H., Huehn, A., O’Connor, G. M., Cooley, S., Miller, J. S., & Anderson, S. K. (2014). Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression. Genes and Immunity, 15(7), 440–448. http://doi.org/10.1038/gene.2014.34
Publisher:
Nature Publishing Group
Journal:
Genes and Immunity
Publication Date:
Oct-2014
URI:
http://hdl.handle.net/10034/604083
DOI:
10.1038/gene.2014.34
Additional Links:
http://www.nature.com/gene/index.html
Type:
Article
Language:
en_US
ISSN:
1466-4879
EISSN:
1476-5470
Appears in Collections:
Biological Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorWright, Paul W.en
dc.contributor.authorLi, Honchuanen
dc.contributor.authorHuehn, Andrewen
dc.contributor.authorO'Connor, Geraldine M.en
dc.contributor.authorCooley, Sarahen
dc.contributor.authorMiller, Jeffrey S.en
dc.contributor.authorAnderson, Stephen K.en
dc.date.accessioned2016-03-31T08:33:26Zen
dc.date.available2016-03-31T08:33:26Zen
dc.date.issued2014-10en
dc.identifier.citationWright, P. W., Li, H., Huehn, A., O’Connor, G. M., Cooley, S., Miller, J. S., & Anderson, S. K. (2014). Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression. Genes and Immunity, 15(7), 440–448. http://doi.org/10.1038/gene.2014.34en
dc.identifier.issn1466-4879en
dc.identifier.doi10.1038/gene.2014.34en
dc.identifier.urihttp://hdl.handle.net/10034/604083en
dc.description.abstractMembers of the human KIR (killer cell immunoglobulin-like receptor) class I major histocompatibility complex receptor gene family contain multiple promoters that determine the variegated expression of KIR on natural killer cells. In order to identify novel genetic alterations associated with decreased KIR expression, a group of donors was characterized for KIR gene content, transcripts and protein expression. An individual with a single copy of the KIR2DL1 gene but a very low level of gene expression was identified. The low expression phenotype was associated with a single-nucleotide polymorphism (SNP) that created a binding site for the inhibitory ZEB1 (Zinc finger E-box-binding homeobox 1) transcription factor adjacent to a c-Myc binding site previously implicated in distal promoter activity. Individuals possessing this SNP had a substantial decrease in distal KIR2DL1 transcripts initiating from a novel intermediate promoter located 230 bp upstream of the proximal promoter start site. Surprisingly, there was no decrease in transcription from the KIR2DL1 proximal promoter. Reduced intermediate promoter activity revealed the existence of alternatively spliced KIR2DL1 transcripts containing premature termination codons that initiated from the proximal KIR2DL1 promoter. Altogether, these results indicate that distal transcripts are necessary for KIR2DL1 protein expression and are required for proper processing of sense transcripts from the bidirectional proximal promoter.en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.relation.urlhttp://www.nature.com/gene/index.htmlen
dc.subjectNatural Killer Cellsen
dc.subjectKIRen
dc.titleCharacterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expressionen_US
dc.typeArticleen
dc.identifier.eissn1476-5470en
dc.contributor.departmentBasic Science Program, Leidos Biomedical Research Inc., Lab of Experimental Immunology, Frederick National Lab, Frederick, MD, USA. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.en
dc.identifier.journalGenes and Immunityen
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