Genomewide approaches for BACH1 target genes in mouse embryonic fibroblasts showed BACH1‐Pparg pathway in adipogenesis

Abstract

The transcription repressor BTB and CNC homology 1 (BACH1) represses genes involved in heme metabolism and oxidative stress response. BACH1 also suppresses the p53-dependent cellar senescence in primary mouse embryonic fibroblasts (MEFs). To investigate the role of BACH1 in MEF other than its known functions, we carried out a genomewide mapping of binding site for BACH1 and its heterodimer partner MAFK in immortalized MEFs (iMEFs) using chromatin immunoprecipitation and next-generation sequencing technology (ChIPsequence). The comparative analysis of the ChIP-sequence data and DNA microarray data from Bach1-deficient and wild-type (WT) iMEF showed 35 novel candidate target genes of BACH1. Among these genes, five genes (Pparg, Nfia, Ptplad2, Adcy1 and Ror1) were related with lipid metabolism. Bach1-deficient iMEFs showed increased expression of mRNA and protein of PPARc, which is the key factor of adipogenesis. These cells also showed a concomitant increase in ligand-dependent activation of PPARc target genes compared with wild-type iMEFs. Moreover, Bach1-deficient iMEFs efficiently differentiated to adipocyte compared with wild-type cells in the presence of PPARc ligands. Our results suggest that BACH1 regulates expression of adipocyte-related genes including Pparg and potentiates adipocyte differentiation capacity.

Bach1: Function, Regulation, and Involvement in Disease

“…Heme-induced Bach1 degradation also promotes the transcription factor SPI-C expression in monocytes and the development of bone marrow macrophages [ 65 ], and when Bach1 was overexpressed (under the control of the GATA-1 promoter) in transgenic mice, megakaryocyte maturation was significantly impaired and the animals developed thrombocytopenia, likely because Bach1 suppressed the expression of p45-targeted genes such as thromboxane synthase [ 66 ]. Bach1 also regulates adipogenesis in primary mouse embryonic fibroblasts by suppressing the expression of peroxisome proliferator-activated receptor (PPAR) γ and PPAR γ -dependent adipocyte differentiation [ 67 ].…”

Bach1 regulates self-renewal and impedes mesendodermal differentiation of human embryonic stem cells

“…Bach1 is highly expressed in mouse embryos ( 20 , 21 ), and mice with homozygous deletions of all Bach1 coding exons are subviable and produced in low numbers. Bach1 also inhibits the differentiation of erythroid cells, macrophages, and adipocytes ( 22 ) and impairs both developmental angiogenesis in zebrafish embryos ( 23 ) and the angiogenic response to peripheral ischemic injury in adult mice ( 24 ), but whether Bach1 participates in the self-renewal and the early differentiation of hESCs remains unknown.…”

Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation

“…Bach1 also represses a portion of p53 target genes by interacting with p53 and histone deacetylase-1 (HDAC1), resulting in inhibition of p53-mediated cellular senescence [ 21 ]. Mapping of Bach1 binding sites on the mouse genome has revealed that Bach1 represses adipocyte differentiation activity of fibroblasts as well [ 22 ]. However, little has been known on the function of Bach1 in the skeletal muscle system.…”