Abstract
Background: Adipose tissue (AT) dysfunction is involved in obesity-related comorbidities. Epigenetic alterations have been recently associated with AT deterioration in obesity conditions. In this work, we profiled the H3K4me3 histone mark in human AT, with special emphasis on the changes in the pattern of histone modification in obesity and insulin resistance (IR). Visceral AT (VAT) was collected and subjected to chromatin immunoprecipitation (ChIP) using anti-H3K4me3 antibody and then sequenced to obtain the H3K4me3 genome profile. Results: We found that most of the H3K4me3 enriched regions were located in gene promoters of pathways related to AT biology and function. H3K4me3 enrichment at gene promoters was strongly related to higher mRNA levels. Differentially expressed genes in AT of patients classified as non-obese, obese with low IR, and obese with high IR could be regulated by differentially enriched H3K4me3; these genes encoded for pathways that could in part explain AT functioning during obesity and insulin resistance (e.g., extracellular matrix organization, PPARG signaling or inflammation). Conclusions: In conclusion, we emphasize the importance of the epigenetic mark H3K4me3 in VAT dysfunction in obesity and IR. The understanding of such mechanisms could give rise to the development of new epigenetic-based pharmacological strategies to ameliorate obesity-related comorbidities.
Highlights
Adipose tissue (AT), traditionally seen as a mere storage tissue [1,2], is nowadays considered as an endocrine organ that can modulate systemic metabolism and energy metabolism in other organs [1,2,3].A dysfunctional AT is believed to be in part responsible for the development of metabolic disorders associated with obesity, and it is thought to increase the risk for obesityrelated diseases, such as diabetes or cancers [4,5]
We found that genes enriched with the H3K4me3 mark were related to pathways involved in AT function and biology (Supplementary Figure S1)
Motif enrichment analysis showed that genomic regions with H3K4me3 modification were enriched for binding sequences of known adipose regulators such as PPARG known to be the key factor in adipogenesis [15,16] and required for adipocyte identity and survival of mature adipocytes; EBF1 and EBF2 are transcription factors necessary for adipogenesis of 3T3-L1 cells [17]
Summary
Adipose tissue (AT), traditionally seen as a mere storage tissue [1,2], is nowadays considered as an endocrine organ that can modulate systemic metabolism and energy metabolism in other organs [1,2,3].A dysfunctional AT is believed to be in part responsible for the development of metabolic disorders associated with obesity, and it is thought to increase the risk for obesityrelated diseases, such as diabetes or cancers [4,5]. Epigenetic mechanisms have recently emerged as important factors involved in metabolic dysfunction in the onset of obesity [6]. In this regard, epigenetics is highly influenced by nutrition, and it has been suggested as a possible causal factor implicated in AT dysfunction in obesity conditions [7]. Despite the central role that epigenetics might exert in AT biology, the chromatin profiling of histone marks in human visceral AT (VAT). Adipose tissue (AT) dysfunction is involved in obesity-related comorbidities. Results: We found that most of the H3K4me enriched regions were located in gene promoters of pathways related to AT biology and function. H3K4me enrichment at gene promoters was strongly related to higher mRNA levels
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