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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205350 | GEO | 2022/07/26

REPOSITORIES: GEO

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Project description:Objective: Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long non-coding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator, with fat depot-specific expression between abdominal subcutaneous adipose tissue (SAT) and gluteal SAT. HOTAIR locates closely with HOXC13, known to strongly associated with human fat distribution. Here, we examined the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis, and hypothesized that HOTAIR-mediated DNA methylation is correlated with transcriptome changes, leading to the regulation of specific genes and the functional pathways. Methods: The expression level of HOTAIR was compared among different fat-depots collected from six healthy, five severe obese, and five uremic subjects, and was correlated with dual-energy x-ray absorptiometry (DXA) defined regional adiposity. The human immortalized preadipocyte was used to assess the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis. The integrative analysis of reduced representation bisulfite sequencing (RRBS) and RNA-sequencing was performed to identify putative genes that are epigenetically regulated by HOTAIR, and the associated signaling pathways. HOTAIR-repressed genes were further validated using RNA/chromatin immunoprecipitation with real-time qPCR and correlated with human body fat distribution. Results: We found that the expression of HOTAIR was high in gluteal SAT, and low in arm/abdominal SAT and visceral (omental) adipose tissue. It could be aberrantly increased in uremic arm SAT. Notably, in severe obese subjects we found that HOTAIR is lowly expressed in abdominal SAT correlating with a higher abdominal adiposity, whereas in uremic patients HOTAIR is highly expressed in arm SAT correlating with lower arm adiposity. HOTAIR overexpression in human immortalized abdominal preadipocyte remarkably suppresses the in vitro adipogenesis. Overall the differentially methylated genes were functionally enriched for nervous system development. We specifically identified 10 HOTAIR-mediated genes showing strong changes of DNA methylation associated with gene expression during abdominal adipogenesis, suggesting potential epigenetic regulation. Two HOTAIR-repressed genes, SLITRK4 and PITPNC1, were further highlighted and validated; presenting an obesity-driven fat-depot specific expression pattern positively correlated with the central body fat distribution. Conclusions: Our study indicated that HOTAIR is an important regulator for abdominal adipogenesis via intricate DNA methylation likely to associate with transcriptional regulation of specific genes, such as SLITRK4 and PITPNC1.

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

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