Abstract
Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes. Through these analyses, we found that in brown adipocytes, brown lineage-specific genes are pre-marked by both H3K4me1 and H3K27me3, and the removal of H3K27me3 at the late stage is necessary but not sufficient to promote brown gene expression, while the pre-deposition of H3K4me1 plays an essential role in poising the brown genes for expression in mature brown cells. Moreover, we identify SOX13 as part of a p38 MAPK dependent transcriptional response mediating early brown cell lineage commitment. We also identify and subsequently validate PIM1, SIX1 and RREB1 as novel regulators promoting brown adipogenesis. Finally, we show that SIX1 binds to adipogenic and brown marker genes and interacts with C/EBPα, C/EBPβ and EBF2, suggesting their functional cooperation during adipogenesis.
Highlights
Obesity and its associated metabolic complications such as diabetes are increasingly responsible for significant economic and social burdens in many countries worldwide
In order to get a better understanding of the molecular mechanisms and transcriptional programs underlying brown adipocyte differentiation, we profiled the epigenomic and PLOS Genetics | DOI:10.1371/journal.pgen
We identified several novel factors involved in brown adipocyte differentiation and showed that the kinase PIM1 and the transcription factors SIX1, SOX13 and RREB1 positively regulate differentiation
Summary
Obesity and its associated metabolic complications such as diabetes are increasingly responsible for significant economic and social burdens in many countries worldwide. Obesity develops when energy intake exceeds energy expenditure, and the current treatments of obesity have been primarily focused on reducing energy intake These measures were largely inefficient in maintaining long-term weight loss [1]. Fat cells are derived from multipotent mesenchymal stem cells (MSCs), which can give rise to muscle, adipose, bone, or cartilage cells when given appropriate environmental cues. These cells can be broadly divided into fat storage cells, such as white adipocytes (WA); and fat burning cells, which include classical and inducible brown adipocytes (BA) ( known as beige or brite adipocytes) [7]. The members of the bone morphogenetic protein (BMP) family, the PPARγ co-factor PGC1α, the transcription factors (TFs) PRDM16, EBF2, KLF11, the protein deacetylase SIRT1, the secreted factors IRISIN and FGF21 as well as lncRNAs Blnc, lncBATE1, and microRNAs miR193/365 have been shown to be essential for thermogenic fat cell recruitment [6, 10,11,12,13]
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