HOTAIR interacts with PRC2 complex regulating the regional preadipocyte transcriptome and human fat distribution

Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA, HOTAIR (HOX transcript antisense RNA), is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 tri-methylation. HOTAIR is also involved in modifying the gluteal adipocyte transcriptome through alternative splicing. Gluteal-specific expression of HOTAIR is maintained by defined regions of open chromatin across the HOTAIR promoter. HOTAIR expression levels can be modified by hormonal (oestrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass in 25,200 individuals). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development. Human immortalized gluteal preadipocytes were transduced with HOTAIR shRNA and transcriptional profiling was performed at Day0, Day4 and Day14 of adipogenic differentiation compared to shControl cells