Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene

Kiara K. Benson, Wenxiang Hu, Angela H. Weller, Alexis H. Bennett, Eric R. Chen, Sumeet A. Khetarpal, Satoshi Yoshino, William P. Bone, Lin Wang, Joshua D. Rabinowitz, Benjamin F. Voight, Raymond E. Soccio

Research output: Contribution to journalArticle

4 Scopus citations

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 Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 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 PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)23232-23242
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number46
DOIs
StatePublished - Nov 12 2019

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Adipocyte browning
  • Genetics of gene regulation
  • Obesity
  • PM20D1
  • PPARγ

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    Benson, K. K., Hu, W., Weller, A. H., Bennett, A. H., Chen, E. R., Khetarpal, S. A., Yoshino, S., Bone, W. P., Wang, L., Rabinowitz, J. D., Voight, B. F., & Soccio, R. E. (2019). Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene. Proceedings of the National Academy of Sciences of the United States of America, 116(46), 23232-23242. https://doi.org/10.1073/pnas.1913199116