Unique role for lncRNA HOTAIR in defining depot-specific gene expression patterns in human adipose-derived stem cells [Research Papers]

Edina Erdos1,2,3,4,6, Adeline Divoux5,6, Katalin Sandor1,2,3,4,6, Laszlo Halasz1,2,3,4, Steven R. Smith5 and Timothy F. Osborne1,2,3,4 1Division of Diabetes Endocrinology and Metabolism, Johns Hopkins University School of Medicine; Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA; 2Department of Medicine, Johns Hopkins University School of Medicine; Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA; 3Department of Biological Chemistry, Johns Hopkins University School of Medicine; Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA; 4Department of Pediatrics, Johns Hopkins University School of Medicine; Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA; 5Translational Research Institute, AdventHealth, Orlando, Florida 32804, USA Corresponding author: tosborn9jh.edu

6 These authors contributed equally to this work.

Abstract

Accumulation of fat above the waist is an important risk factor in developing obesity-related comorbidities independently of BMI or total fat mass. Deciphering the gene regulatory programs of the adipose tissue precursor cells within upper body or abdominal (ABD) and lower body or gluteofemoral (GF) depots is important to understand their differential capacity for lipid accumulation, maturation, and disease risk. Previous studies identified the HOX transcript antisense intergenic RNA (HOTAIR) as a GF-specific lncRNA; however, its role in adipose tissue biology is still unclear. Using three different approaches (silencing of HOTAIR in GF human adipose-derived stem cells [GF hASCs], overexpression of HOTAIR in ABD hASCs, and ChIRP-seq) to localize HOTAIR binding in GF hASC chromatin, we found that HOTAIR binds and modulates expression, both positively and negatively, of genes involved in adipose tissue-specific pathways, including adipogenesis. We further demonstrate a direct interaction between HOTAIR and genes with high RNAPII binding in their gene bodies, especially at their 3′ ends or transcription end sites. Computational analysis suggests HOTAIR binds preferentially to the 3′ ends of genes containing predicted strong RNA–RNA interactions with HOTAIR. Together, these results reveal a unique function for HOTAIR in hASC depot-specific regulation of gene expression.

Received January 19, 2022. Accepted May 12, 2022.

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