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

TitleNatural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene.
Publication TypeJournal Article
Year of Publication2019
AuthorsBenson, KK, Hu, W, Weller, AH, Bennett, AH, Chen, ER, Khetarpal, SA, Yoshino, S, Bone, WP, Wang, L, Rabinowitz, JD, Voight, BF, Soccio, RE
JournalProc Natl Acad Sci U S A
Volume116
Issue46
Pagination23232-23242
Date Published2019 Nov 12
ISSN1091-6490
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.

DOI10.1073/pnas.1913199116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID31659023
PubMed Central IDPMC6859347
Grant ListR56 DK101478 / DK / NIDDK NIH HHS / United States
K08 DK094968 / DK / NIDDK NIH HHS / United States
R01 DK101478 / DK / NIDDK NIH HHS / United States
R01 DK049780 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States