Functional evaluation of the human fat distribution HOXC13 gene locus

• Main Author: Kuo, Feng-Chih
• Other Authors: Pinnick, Katherine ; Karpe, Fredrik
• Published: University of Oxford 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.757947

Gynoid fat distinguishes from android fat in developmental origin and possesses metabolically protective roles, especially in women. Growing evidence supports that epigenetic modifications could potentially explain the regional differences between fat depots. Recent progress in transcriptome analysis has revealed that long non-coding RNAs (lncRNAs) play roles in epigenetic regulation, but their potential functions in fat depot-specific transcription remain largely unexplored. HOX transcript antisense RNA (HOTAIR) is a lncRNA that is expressed exclusively in the gluteal subcutaneous adipose tissue (GSAT); it is undetectable in the abdominal subcutaneous adipose tissue (ASAT) and locates under the fat distribution - genome-wide association studies (GWAS) locus near and around the HOXC13 gene. Therefore, the aim of this project was to investigate the depot-specific functional roles of the HOTAIR gene. GSAT HOTAIR expression was highly variable between individuals but generally expressed at lower levels in females compared with men. Detailed annotation of HOTAIR-haplotype tagging single nucleotide polymorphisms (SNPs) identified the minor allele of rs76084431 as a GSAT HOTAIR expression quantitative trait locus (eQTL) associated with increased android to gynoid fat mass ratio in females. Comparison of histone marks between abdominal and gluteal preadipocytes showed that rs76084431 is positioned in an open chromatin region and which could be considered as a HOTAIR enhancer in gluteal preadipocytes. HOTAIR stable knockdown and constitutive overexpression in human adipocytes provided further evidence that the HOTAIR gene is essential for the gluteal adipocytes, but anti-adipogenic for abdominal adipocytes. Weighted Gene Co-expression Network Analysis (WGCNA) of RNA-seq from HOTAIR knockdown cells data suggested regulation a number of regulated pathways: extracellular matrix and protocadherin genes appear to be predominant HOTAIR downstream pathways in the gluteal preadipocytes. CEBPD, PTEN and PCDH10 were shown to be epigenetically regulated by HOTAIR during adipogenic differentiation of the gluteal preadipocytes. Overall, these data suggest that HOTAIR is a novel and dynamic regulator of the adipocyte epigenome with functional importance for regional human adipose tissues.