Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis

Kristina M Garske, Caroline Comenho, David Z Pan, Marcus Alvarez, Karen Mohlke, Markku Laakso, Kirsi H Pietiläinen, Päivi Pajukanta.
Epigenetics. 2022-12-01;17(13):1849-1862.
Obesity perturbs central functions of human adipose tissue, centred on differentiation of preadipocytes to adipocytes, i.e., adipogenesis. The large environmental component of obesity makes it important to elucidate epigenetic regulatory factors impacting adipogenesis. Promoter Capture Hi-C (pCHi-C) has been used to identify chromosomal interactions between promoters and associated regulatory elements. However, long range interactions (LRIs) greater than 1 Mb are often filtered out of pCHi-C datasets, due to technical challenges and their low prevalence. To elucidate the unknown role of LRIs in adipogenesis, we investigated preadipocyte differentiation to adipocytes using pCHi-C and bulk and single nucleus RNA-seq data. We first show that LRIs are reproducible between biological replicates, and they increase >2-fold in frequency across adipogenesis. We further demonstrate that genomic loci containing LRIs are more epigenetically repressed than regions without LRIs, corresponding to lower gene expression in the LRI regions. Accordingly, as preadipocytes differentiate into adipocytes, LRI regions are more likely to contain repressed preadipocyte marker genes; whereas these same LRI regions are depleted of actively expressed adipocyte marker genes. Finally, we show that LRIs can be used to restrict multiple testing of the long-range cis-eQTL analysis to identify variants that regulate genes via LRIs. We exemplify this by identifying a putative long range cis regulatory mechanism at the LYPLAL1/TGFB2 obesity locus. In summary, we identify LRIs that mark repressed regions of the genome, and these interactions increase across adipogenesis, pinpointing developmental regions that need to be repressed in a cell-type specific way for adipogenesis to proceed.
Consortium data used in this publication
The PAd and Diff pCHi-C data and PAd, Diff and Adip ATAC-seq data are available at GEO under accession number GSE129574. The Adip pCHi-C data are available at GEO under accession number GSE129574.

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Assay for transposase accessible chromatin (ATAC) -seq libraries were produced from human primary preadipocytes (PAd), in vitro differntiated human adipocytes (Ad), and in vitro differentiated human adipocytes that were exposed to 200 uM palmitic acid, 200 uM oleic acid, or BSA control (all with n=3 independent replicates). Promoter Capture Hi-C libraries were produced from in vitro differentiated human white adipocytes that were exposed to 200 uM palmitic acid, 200 uM oleic acid, or BSA control (all with n=2 independent replicates).