Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis
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)...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2022.2088145 |
| _version_ | 1827811476068368384 |
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| author | Kristina M. Garske Caroline Comenho David Z. Pan Marcus Alvarez Karen Mohlke Markku Laakso Kirsi H. Pietiläinen Päivi Pajukanta |
| author_facet | Kristina M. Garske Caroline Comenho David Z. Pan Marcus Alvarez Karen Mohlke Markku Laakso Kirsi H. Pietiläinen Päivi Pajukanta |
| author_sort | Kristina M. Garske |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:05:38Z |
| format | Article |
| id | doaj.art-8b05b59ad3c34da58b79e4dfb81439c3 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:05:38Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-8b05b59ad3c34da58b79e4dfb81439c32023-09-21T13:23:12ZengTaylor & Francis GroupEpigenetics1559-22941559-23082022-12-0117131849186210.1080/15592294.2022.20881452088145Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesisKristina M. Garske0Caroline Comenho1David Z. Pan2Marcus Alvarez3Karen Mohlke4Markku Laakso5Kirsi H. Pietiläinen6Päivi Pajukanta7David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLAUniversity of North CarolinaInstitute of Clinical Medicine, University of Eastern Finland and Kuopio University HospitalUniversity of HelsinkiDavid Geffen School of Medicine at UCLAObesity 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.http://dx.doi.org/10.1080/15592294.2022.2088145adipogenesisobesitychromosomal interactions |
| spellingShingle | Kristina M. Garske Caroline Comenho David Z. Pan Marcus Alvarez Karen Mohlke Markku Laakso Kirsi H. Pietiläinen Päivi Pajukanta Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis Epigenetics adipogenesis obesity chromosomal interactions |
| title | Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| title_full | Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| title_fullStr | Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| title_full_unstemmed | Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| title_short | Long-range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| title_sort | long range chromosomal interactions increase and mark repressed gene expression during adipogenesis |
| topic | adipogenesis obesity chromosomal interactions |
| url | http://dx.doi.org/10.1080/15592294.2022.2088145 |
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