skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: A Long Non-coding RNA, LOC157273, Is an Effector Transcript at the Chromosome 8p23.1-PPP1R3B Metabolic Traits and Type 2 Diabetes Risk Locus

Journal Article · · Frontiers in Genetics
 [1];  [2];  [3];  [3];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [10];  [11];  [12]
  1. Massachusetts General Hospital, Boston, MA (United States). Mongan Inst. Clinical and Translational Epidemiology Unit; Harvard Medical School, Boston, MA (United States). Dept. of Medicine; Broad Inst. of MIT and Harvard, Cambridge, MA (United States). Programs in Metabolism and Medical & Population Genetics
  2. Wayne State Univ., Detroit, MI (United States). Center for Molecular Medicine & Genetics
  3. Wayne State Univ., Detroit, MI (United States). Center for Molecular Medicine & Genetics
  4. Wayne State Univ., Detroit, MI (United States). Center for Molecular Medicine & Genetics; Wayne State Univ., Detroit, MI (United States). Karmanos Cancer Inst.
  5. Broad Inst. of MIT and Harvard, Cambridge, MA (United States). Programs in Metabolism and Medical & Population Genetics; Massachusetts General Hospital, Boston, MA (United States). Center for Genomic Medicine; Massachusetts General Hospital, Boston, MA (United States). Division of General Internal Medicine
  6. Massachusetts General Hospital, Boston, MA (United States). Center for Genomic Medicine; Massachusetts General Hospital, Boston, MA (United States). Diabetes Unit
  7. Univ. of California, Berkeley, CA (United States). Dept. of Statistics; Univ. of Birmingham (United Kingdom). Centre for Computational Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biosciences Area. Computational Biosciences Group
  8. Cedars-Sinai Medical Center, Los Angeles, CA (United States). Dept. of Medicine. Division of Endocrinology, Diabetes, and Metabolism
  9. The Lundquist Inst. for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (United States). Dept. of Pediatrics. The Inst. for Translational Genomics and Population Sciences
  10. McGill Univ., Montreal, QC (Canada). Dept. of Human Genetics; McGill Univ., Montreal, QC (Canada). Dept. of medicine; McGill Univ. and Genome Québec Innovation Centre, Montréal, QC (Canada)
  11. Harvard Medical School, Boston, MA (United States). Dept. of Medicine; Broad Inst. of MIT and Harvard, Cambridge, MA (United States). Programs in Metabolism and Medical & Population Genetics; Massachusetts General Hospital, Boston, MA (United States). Division of General Internal Medicine
  12. Wayne State Univ., Detroit, MI (United States). Center for Molecular Medicine & Genetics; Wayne State Univ., Detroit, MI (United States). School of Medicine. Dept. of Neurology
+ Show Author Affiliations

Causal transcripts at genomic loci associated with type 2 diabetes (T2D) are mostly unknown. The chr8p23.1 variant rs4841132, associated with an insulin-resistant diabetes risk phenotype, lies in the second exon of a long non-coding RNA (lncRNA) gene, LOC157273, located 175 kilobases from PPP1R3B, which encodes a key protein regulating insulin-mediated hepatic glycogen storage in humans. We hypothesized that LOC157273 regulates expression of PPP1R3B in human hepatocytes. We tested our hypothesis using Stellaris fluorescent in situ hybridization to assess subcellular localization of LOC157273; small interfering RNA (siRNA) knockdown of LOC157273, followed by RT-PCR to quantify LOC157273 and PPP1R3B expression; RNA-seq to quantify the whole-transcriptome gene expression response to LOC157273 knockdown; and an insulin-stimulated assay to measure hepatocyte glycogen deposition before and after knockdown. We found that siRNA knockdown decreased LOC157273 transcript levels by approximately 80%, increased PPP1R3B mRNA levels by 1.7-fold, and increased glycogen deposition by >50% in primary human hepatocytes. An A/G heterozygous carrier (vs. three G/G carriers) had reduced LOC157273 abundance due to reduced transcription of the A allele and increased PPP1R3B expression and glycogen deposition. We show that the lncRNA LOC157273 is a negative regulator of PPP1R3B expression and glycogen deposition in human hepatocytes and a causal transcript at an insulin-resistant T2D risk locus.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1816102
Journal Information:
Frontiers in Genetics, Vol. 11; ISSN 1664-8021
Publisher:
Frontiers Media S.A.Copyright Statement
Country of Publication:
United States
Language:
English

References (56)

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease journal April 2018
The 9p21 Locus and its Potential Role in Atherosclerosis Susceptibility; Molecular Mechanisms and Clinical Implications journal November 2016
The twentieth century struggle to decipher insulin signalling journal November 2006
Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1 journal December 2000
Sense-antisense gene pairs: sequence, transcription, and structure are not conserved between human and mouse journal January 2013
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance journal May 2012
Genome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation? journal March 2017
Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants journal January 2014
A new shrinkage estimator for dispersion improves differential expression detection in RNA-seq data journal September 2012
Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin journal July 2016
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly journal July 2015
Biological, clinical and population relevance of 95 loci for blood lipids journal August 2010
Differential expression analysis for sequence count data journal October 2010
Long Non-coding RNAs as Local Regulators of Pancreatic Islet Transcription Factor Genes journal November 2018
Long Noncoding RNAs with Enhancer-like Function in Human Cells journal October 2010
Distinctive Regulatory and Metabolic Properties of Glycogen-targeting Subunits of Protein Phosphatase-1 (PTG, GL, GM/RGl) Expressed in Hepatocytes journal August 2000
A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus journal July 2017
Long noncoding RNA variations in cardiometabolic diseases journal June 2016
Impact of Recent Increase in Incidence on Future Diabetes Burden: U.S., 2005-2050 journal August 2006
RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol journal June 2016
ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization journal January 2016
βlinc1 encodes a long noncoding RNA that regulates islet β-cell formation and function journal March 2016
Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium. journal March 1996
A Microassay for Measuring Glycogen in 96-Well-Cultured Cells journal May 1996
Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries journal June 2018
A promoter-level mammalian expression atlas journal March 2014
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility journal January 2015
Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies journal July 2013
Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project journal February 2011
GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study journal October 2015
Examination of PPP1R3B as a candidate gene for the type 2 diabetes and MODY loci on chromosome 8p23: PPP1R3B in type 2 diabetes and MODY journal August 2006
A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure journal March 2018
The genetic architecture of type 2 diabetes journal July 2016
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps journal October 2018
Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis journal August 2012
Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease journal January 2014
Complex Loci in Human and Mouse Genomes journal January 2006
Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation journal January 2012
The genetic regulatory signature of type 2 diabetes in human skeletal muscle journal June 2016
A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression journal April 2018
Genetic regulatory signatures underlying islet gene expression and type 2 diabetes journal February 2017
Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors journal December 2015
Role of glycogen phosphorylase in liver glycogen metabolism journal December 2015
Reversal of Diet-induced Glucose Intolerance by Hepatic Expression of a Variant Glycogen-targeting Subunit of Protein Phosphatase-1 journal January 2002
Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes journal April 2018
The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study journal May 2013
Human β Cell Transcriptome Analysis Uncovers lncRNAs That Are Tissue-Specific, Dynamically Regulated, and Abnormally Expressed in Type 2 Diabetes journal October 2012
The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies journal May 2008
Pleiotropy among Common Genetic Loci Identified for Cardiometabolic Disorders and C-Reactive Protein journal March 2015
Amino acid sequence and expression of the hepatic glycogen-binding (G L -subunit of protein phosphatase-1 journal November 1995
Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction journal October 2006
Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks journal February 2017
Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes journal January 2019
Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits journal March 2011
Diabetes Incidence in pima Indians: Contributions of Obesity and Parental Diabetes1 journal February 1981
Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride journal April 2018

Similar Records

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Journal Article · Thu Jan 29 00:00:00 EST 2015 · Nature Communications · OSTI ID:1816102
+201 more
Targeting long non-coding RNA ASBEL with oligonucleotide antagonist for breast cancer therapy
Journal Article · Sat Aug 05 00:00:00 EDT 2017 · Biochemical and Biophysical Research Communications · OSTI ID:1816102
+4 more
LncRNA MALAT1 is up-regulated in diabetic gastroparesis and involved in high-glucose-induced cellular processes in human gastric smooth muscle cells
Journal Article · Thu Feb 15 00:00:00 EST 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1816102
+5 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
insulin resistance
hepatic glycogen storage
long non-coding RNA
metabolism
type 2 diabetes
regulatory mechanisms