Postdoc - Biomedicine

Transcriptional Regulation of Autophagy During Adipocyte Differentiation


Summary

Public repositories were surveyed for high-throughput sequencing data on the in vitro adipocyte model 3T3-L1 and curated extensive metadata on the included samples. The raw data were collected and processed using standard pipelines. These datasets were used to construct models for gene expression and DNA-binding in the differentiating 3T3-L1. The processed data was documented and made available as open-source Bioconductor experimental data packages. The models were assessed for quality and were found to reflect essential aspects of known adipocyte biology from the published literature and the human primary adipocytes.

Autophagy genes are regulated as part of the differentiation course of the adipocytes. This is evident by the global expression profiles and key autophagy gene markers. Adipogenic transcription factors such as CEBPB and PPARG drive this regulation. The adipogenic factors target key autophagy genes such as Becn1, Map1lc3b, and Sqstm1. Moreover, other autophagy genes are regulated indirectly through autophagy transcription factors Foxo1, Tfeb, and Xbp1. Co-factors such as MED1 are actively contributing to the adipogenic transcription factors' binding sites on autophagy genes. Other co-factors such as RXRG and EP300 have their contributions more specific to the targets of PPARG or CEBPB, respectively. Enhancer region histone markers H3K4me1 and H3K27ac also associate with the adipogenic factors, which might indicate non-transcriptional roles such as organizing the chromatin regions containing autophagy coding genes.

Regulation of autophagy genes by adipogenic transcription factors. Adipogenic transcription factors (CEBPB and PPARG) regulate autophagy genes during adipogenesis in two different ways. First, the factors bind directly to key autophagy genes such as Map1lc3, Becn1, and Sqstm1 and induce their expression. Second, the factors induce the expression of genes coding for autophagy specific transcription factors such as Xbp1, Foxo1, and Tfeb. Those factors target downstream genes in the autophagy pathway. The adipogenic transcription factors' functions are modulated by co-factors such as MED1, RXRG, and EP300.