Journal article
Natural human genetic variation determines basal and inducible expression of PM20D1 , an obesity-associated gene
Proceedings of the National Academy of Sciences - PNAS, v 116(46), pp 23232-23242
12 Nov 2019
PMID: 31659023
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce
expression in mouse adipocytes. In contrast,
is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene's transcription start site (TSS) in human but not mouse adipocytes. The -4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of
in adipocytes, distinct variants downstream of the TSS have strong effects on
expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low
expression and correspondingly high DNA methylation at the TSS. These
low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.
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Details
- Title
- Natural human genetic variation determines basal and inducible expression of PM20D1 , an obesity-associated gene
- Creators
- Kiara K Benson - University of PennsylvaniaWenxiang Hu - University of PennsylvaniaAngela H Weller - University of PennsylvaniaAlexis H Bennett - University of PennsylvaniaEric R Chen - University of PennsylvaniaSumeet A Khetarpal - University of PennsylvaniaSatoshi Yoshino - University of PennsylvaniaWilliam P Bone - University of PennsylvaniaLin Wang - Princeton UniversityJoshua D Rabinowitz - Princeton UniversityBenjamin F Voight - University of PennsylvaniaRaymond E Soccio - University of PennsylvaniaXiaohua Hu - Information Science (Informatics)
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 116(46), pp 23232-23242
- Publisher
- PNAS
- Grant note
- R01 DK101478 / NIDDK NIH HHS P30 DK019525 / NIDDK NIH HHS R56 DK101478 / NIDDK NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Information Science
- Web of Science ID
- WOS:000496506600055
- Scopus ID
- 2-s2.0-85074901157
- Other Identifier
- 991019167525904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity