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

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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.

OriginalsprogEngelsk
Artikelnummer111136
TidsskriftCell Reports
Vol/bind40
Udgave nummer4
Antal sider23
ISSN2211-1247
DOI
StatusUdgivet - 26. jul. 2022

Bibliografisk note

Funding Information:
We thank all the volunteers, general practitioners, and clinical staff for their assistance. We thank Sandy Humphreys, Amy Barrett, and Anita L. Sørensen for sample analysis. This work was funded by the British Heart Foundation (RG/17/1/32663). F.-C.K. was funded by the Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan. The Fenland Study and genetic analyses were funded by the Medical Research Council (MRC) (MC_UU_12015/1) (MC_PC_13046). EPIC-Norfolk and genetic analyses were funded by the MRC (MR/N003284/1) (MC_PC_13048) and Cancer Research United Kingdom (14136). The ORCADES study was supported by the Chief Scientist Office of the Scottish Government, the MRC, the European Union Framework Programme 6, the MS Society UK, the Volant Trust, and the Royal Society. Research was conducted using the UK Biobank resource (application no. 12885). L.B.L.W. acknowledges funding by the Wellcome Trust (WT083442AIA). A.D.v.D. was funded as a Novo Nordisk Oxford University fellow. The graphical abstract was created with BioRender.com. Conceptualization, F.K. K.E.P. and F.-C.K.; methodology, F.-C.K. M.J.N. and N.Y.L.; investigation, F.-C.K. M.J.N. R.S. A.D.v.D. N.Y.L. M.T. N.D. K.E.P. P.C. and C.C.; validation, F.-C.K. R.S. and K.E.P.; data curation, M.J.N. and D.P.; resources, C.L. and P.K.J.; formal analysis, F.-C.K. A.W.-A. D.P. L.B.L.W. and K.A.K.; writing – review & editing, F.K. K.E.P. and F.-C.K. with input from all of the co-authors. The authors declare no competing interests.

Funding Information:
We thank all the volunteers, general practitioners, and clinical staff for their assistance. We thank Sandy Humphreys, Amy Barrett, and Anita L. Sørensen for sample analysis. This work was funded by the British Heart Foundation ( RG/17/1/32663 ). F.-C.K. was funded by the Tri-Service General Hospital , National Defence Medical Centre , Taipei, Taiwan. The Fenland Study and genetic analyses were funded by the Medical Research Council (MRC) ( MC_UU_12015/1 ) ( MC_PC_13046 ). EPIC-Norfolk and genetic analyses were funded by the MRC ( MR/N003284/1 ) ( MC_PC_13048 ) and Cancer Research United Kingdom ( 14136 ). The ORCADES study was supported by the Chief Scientist Office of the Scottish Government , the MRC , the European Union Framework Programme 6, the MS Society UK , the Volant Trust , and the Royal Society . Research was conducted using the UK Biobank resource (application no. 12885). L.B.L.W. acknowledges funding by the Wellcome Trust ( WT083442AIA ). A.D.v.D. was funded as a Novo Nordisk Oxford University fellow. The graphical abstract was created with BioRender.com .

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