Plasticity and expanding complexity of the hepatic transcription factor network during liver development

Abstract

Cross-regulatory cascades between hepatic transcription factors have been implicated in the determination of the hepatic phenotype. Analysis of recruitments to regulatory regions and the temporal and spatial expression pattern of the main hepatic regulators during liver development revealed a gradual increase in complexity of autoregulatory and cross-regulatory circuits. Within these circuits we identified a core group of six transcription factors, which regulate the expression of each other and the expression of other downstream hepatic regulators. Changes in the promoter occupancy patterns during development included new recruitments, release, and exchange of specific factors. We also identified promoter and developmental stage-specific dual regulatory functions of certain factors as an important feature of the network. Inactivation of HNF-4␣ in embryonic, but not in adult, liver resulted in the diminished expression of most hepatic factors, demonstrating that the stability of the network correlates with its complexity. The results illustrate the remarkable flexibility of a self-sustaining transcription factor network, built up by complex dominant and redundant regulatory motifs in developing hepatocytes.[Keywords: Hepatocyte development; transcription factor; regulatory network] Supplemental material is available at http://www.genesdev.org.

High-resolution mapping of transcriptional dynamics across tissue development reveals a stable mRNA–tRNA interface

“…The widespread changes in protein-coding gene expression occurring during mammalian development have been previously explored using gene-specific (Wutz et al 1997;Kyrmizi et al 2006;Mallo and Alonso 2013) and transcriptome-wide approaches (Bruneau 2008;Kang et al 2011;Nord et al 2013). Here, we confirmed that liver and brain development are accompanied by thousands of protein-coding transcript changes, which accurately reflect the tissue and stage identity of all samples.…”

“…The direct interaction of these transcripts produced by Pol II and Pol III is a vital step in the flow of genetic information, in which the triplet codons in mRNAs are selectively identified by their counterpart tRNA anticodons to direct protein synthesis. To explore the largely unknown regulatory mechanisms active at this mRNA-tRNA interface, we exploited the rapid and extensive changes in the transcriptome occurring among different developmental stages of mammalian organogenesis (Kyrmizi et al 2006;Kang et al 2011;Lee et al 2012;Liscovitch and Chechik 2013;Sunkin et al 2013).…”

Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles

“…As a result, Foxa2, Hnf4a, Foxa3, and Hnf1a (Fig. S7J and Dataset S8), which play pivotal roles in the maintenance and induction of the transcriptional profile of hepatic-lineage cells (31)(32)(33), were significantly enriched with respect to other TFs, as based on the interference scores (P < 10 −4 , Student t test). The interfering TFs in the hepatoblasts did not show interference in the NSEB5-2C cells, and the interfering TFs in the NSEB5-2C cells also did not show interference in hepatoblasts (Fig.…”

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

“…Similarly, we could detect distal region sequences in anti-HNF4␣, anti-CBP, and anti-RNA Pol-II immunoprecipitates only in cells treated with GW4064. The simultaneous presence of the two DNA fragments in these immunoprecipitates demonstrates that the upstream and downstream regions come into close proximity, allowing their efficient cross-linking (11,31). This physical association of the two regions requires GPS2, because HNF4␣, CBP, and Pol-II ChIP signals at the upstream region or FXR ChIP signal at the downstream region were greatly reduced in GW4064-treated GPS2 knockdown cells.…”