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

Feng-Chih Kuo; Matt J Neville; Rugivan Sabaratnam; Agata Wesolowska-Andersen; Daniel Phillips; Laura B L Wittemans; Andrea D van Dam; Nellie Y Loh; Marijana Todorčević; Nathan Denton; Katherine A Kentistou; Peter K Joshi; Constantinos Christodoulides; Claudia Langenberg; Philippe Collas; Fredrik Karpe; Katherine E Pinnick

doi:10.1016/j.celrep.2022.111136

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

Cell Rep. 2022 Jul 26;40(4):111136. doi: 10.1016/j.celrep.2022.111136.

Authors

Feng-Chih Kuo¹, Matt J Neville², Rugivan Sabaratnam³, Agata Wesolowska-Andersen⁴, Daniel Phillips⁵, Laura B L Wittemans⁶, Andrea D van Dam⁵, Nellie Y Loh⁵, Marijana Todorčević⁵, Nathan Denton⁵, Katherine A Kentistou⁷, Peter K Joshi⁸, Constantinos Christodoulides⁵, Claudia Langenberg⁹, Philippe Collas¹⁰, Fredrik Karpe¹¹, Katherine E Pinnick¹²

Affiliations

¹ Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan.
² Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Oxford, UK.
³ Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark; Steno Diabetes Center Odense, Odense University Hospital, 5000 Odense C, Denmark.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
⁵ Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK.
⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK; The Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁷ Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
⁸ Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
⁹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
¹⁰ Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital, Oslo, Norway.
¹¹ Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Oxford, UK. Electronic address: fredrik.karpe@ocdem.ox.ac.uk.
¹² Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK. Electronic address: katherine.pinnick@ocdem.ox.ac.uk.

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 we identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 trimethylation. 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 (estrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development.

Keywords: CP: Molecular biology; HOTAIR; adipogenesis; epigenetic regulation; fat distribution; lncRNA; subcutaneous adipose tissue.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatin
Estrogens
Humans
Polycomb Repressive Complex 2* / genetics
Polycomb Repressive Complex 2* / metabolism
Promoter Regions, Genetic / genetics
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
Transcriptome / genetics

Substances

Chromatin
Estrogens
HOTAIR long untranslated RNA, human
RNA, Long Noncoding
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding