title: Persistent transcriptional responses show the involvement of feed-forward control in a repeated dose toxicity study.
abstract: Chemical carcinogenesis, albeit complex, often relies on modulation of transcription through activation or repression of key transcription factors. While analyzing extensive networks may hinder the biological interpretation, one may focus on dynamic network motifs, among which persistent feed-forward loops (FFLs) are known to chronically influence transcriptional programming. Here, to investigate the relevance a FFL-oriented approach in depth, we have focused on aflatoxin B1-induced transcriptomic alterations during distinct states of exposure (daily administration during 5days followed by a non-exposed period) of human hepatocytes, by exploring known interactions in human transcription. Several TF-coding genes were persistently deregulated after washout of AFB1. Oncogene MYC was identified as the prominent regulator and driver of many FFLs, among which a FFL comprising MYC/HIF1A was the most recurrent. The MYC/HIF1A FFL was also identified and validated in an independent set as the master regulator of metabolic alterations linked to initiation and progression of carcinogenesis, i.e. the Warburg effect, possibly as result of persistent intracellular alterations arising from AFB1 exposure (nuclear and mitochondrial DNA damage, oxidative stress, transcriptional activation by secondary messengers). In summary, our analysis shows the involvement of FFLs as modulators of gene expression suggestive of a carcinogenic potential even after termination of exposure.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands. Electronic address: t.souza@maastrichtuniversity.nl.
authors.forename: Terezinha M
authors.initials: TM
authors.lastname: Souza
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands. Electronic address: linda.rieswijk@maastrichtuniversity.nl.
authors.forename: Linda
authors.initials: L
authors.lastname: Rieswijk
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands. Electronic address: t.vandenbeucken@maastrichtuniversity.nl.
authors.forename: Twan van den
authors.initials: TV
authors.lastname: Beucken
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands. Electronic address: j.kleinjans@maastrichtuniversity.nl.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands. Electronic address: danyel.jennen@maastrichtuniversity.nl.
authors.forename: Danyel
authors.initials: D
authors.lastname: Jennen
mesh_terms: D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D014157:Transcription Factors; D016604:Aflatoxin B1
keywords: Aflatoxin B1; Feed-forward loop; Hepatocellular carcinoma; Network motif; Transcription factor