PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most extensively studied ligand-inducible transcription factors (TFs), able to modulate its transcriptional activity through conformational changes. It is of particular interest because of its pleiotropic functions: it plays a crucial role in the expression of key genes involved in adipogenesis, lipid and glucid metabolism, atherosclerosis, inflammation, and cancer. Its protein isoforms, the wide number of PPARγ target genes, ligands, and coregulators contribute to determine the complexity of its function. In addition, the presence of genetic variants is likely to affect expression levels of target genes although the impact of PPARG gene variations on the expression of target genes is not fully understood. The introduction of massively parallel sequencing platforms—in the Next Generation Sequencing (NGS) era—has revolutionized the way of investigating the genetic causes of inherited diseases. In this context, DNA-Seq for identifying—within both coding and regulatory regions of PPARG gene—novel nucleotide variations and haplotypes associated to human diseases, ChIP-Seq for defining a PPARγ binding map, and RNA-Seq for unraveling the wide and intricate gene pathways regulated by PPARG, represent incredible steps toward the understanding of PPARγ in health and disease.

Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder

“…34,37 There was only one significant result in our sample, and it is consistent with the above-mentioned findings: the child/ adolescent population with the PRO/ALA genotype had lower BP values than those recorded in the PRO/PRO group.…”

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…To this purpose, a growing number of studies is currently showing that the integration of data derived from ChIP-(and its subapplications such as MeDIP-Seq or Methyl-Seq) and RNA-Seq analyses is the way forward. 86 Systematically profiling epigenome and transcriptome in multiple cell types and stages -in both physiological and pathological states -will improve the understanding of developmental processes and disease onset. 86,87 RNA-SEQ LIMITATIONS AND ISSUES After the 'early days enthusiasm' RNA-Seq has revealed its pitfalls, from sample preparation to data analysis, showing an obscuring variability.…”

“…86 Systematically profiling epigenome and transcriptome in multiple cell types and stages -in both physiological and pathological states -will improve the understanding of developmental processes and disease onset. 86,87 RNA-SEQ LIMITATIONS AND ISSUES After the 'early days enthusiasm' RNA-Seq has revealed its pitfalls, from sample preparation to data analysis, showing an obscuring variability. 88 Criticism about the experimental design and the validation issues in RNA-Seq experiments are now emerging in the literature, and different strategies to avoid -or at least to controlsome unwanted effects have been proposed.…”

Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

“…Another SLCO1B1 variant, rs4149015, known to affect its own expression [68], may impact its transporting activity and, consequently, drug response. Variants in PPARG2 have been known to affect mRNA expression of PPARG1 and its target genes [69,70], which play a diverse role in cellular energy metabolism and angiogenesis. Activation of PPARb/d, in particular, has been reported to favor angiogenesis, and is suggested to play a critical role in inducing angiogenesis in pancreatic cancer [71].…”