Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes

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Pan , D Z , Miao , Z , Comenho , C , Rajkumar , S , Koka , A , Lee , S H T , Alvarez , M , Kaminska , D , Ko , A , Sinsheimer , J S , Mohlke , K L , Mancuso , N , Munoz-Hernandez , L L , Herrera-Hernandez , M , Tusie-Luna , M T , Aguilar-Salinas , C , Pietiläinen , K H , Pihlajamäki , J , Laakso , M , Garske , K M & Pajukanta , P 2021 , ' Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes ' , Genome medicine , vol. 13 , no. 1 , 123 . https://doi.org/10.1186/s13073-021-00939-2

Title: Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes
Author: Pan, David Z.; Miao, Zong; Comenho, Caroline; Rajkumar, Sandhya; Koka, Amogha; Lee, Seung Hyuk T.; Alvarez, Marcus; Kaminska, Dorota; Ko, Arthur; Sinsheimer, Janet S.; Mohlke, Karen L.; Mancuso, Nicholas; Munoz-Hernandez, Linda Liliana; Herrera-Hernandez, Miguel; Tusie-Luna, Maria Teresa; Aguilar-Salinas, Carlos; Pietiläinen, Kirsi H.; Pihlajamäki, Jussi; Laakso, Markku; Garske, Kristina M.; Pajukanta, Päivi
Contributor: University of Helsinki, HUS Abdominal Center
Date: 2021-08-02
Language: eng
Number of pages: 20
Belongs to series: Genome medicine
ISSN: 1756-994X
URI: http://hdl.handle.net/10138/334906
Abstract: Background: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n similar to 1400) and WHRadjBMI GWAS data (n similar to 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
Subject: Transcriptional regulation of abdominal obesity
Master transcription factor
Trans regulation of genes
Waist-hip ratio adjusted for body mass index (WHRadjBMI)
Type 2 diabetes (T2D)
Polygenic risk score (PRS)
GENOME-WIDE ASSOCIATION
WAIST-HIP RATIO
FAT DISTRIBUTION
AMINO-ACIDS
RNA-SEQ
EXPRESSION
ELEMENTS
WEIGHT
POWER
LOCI
3121 General medicine, internal medicine and other clinical medicine
1184 Genetics, developmental biology, physiology
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