A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver

Anjana Ramdas Nair, Priyanka Lakhiani, Chi Zhang, Filippo Macchi, Kirsten C. Sadler

Research output: Contribution to journalArticlepeer-review

Abstract

Restoring homeostasis following proteostatic stress hinges on a stress-specific transcriptional signature. How these signatures are regulated is unknown. We use functional genomics to uncover how activating transcription factor 6 (ATF6), a central factor in the unfolded protein response, regulates its target genes in response to toxicant induced and physiological stress in the liver. We identified 652 conserved putative ATF6 targets (CPATs), which functioned in metabolism, development and proteostasis. Strikingly, Atf6 activation in the zebrafish liver by transgenic nAtf6 overexpression, ethanol and arsenic exposure resulted in a distinct CPAT signature for each; with only 34 CPATs differentially expressed in all conditions. In contrast, during liver regeneration in mice resulted in a dynamic differential expression pattern of 53% of CPATs. These CPATs were distinguished by residing in open chromatin, H3K4me3 occupancy and the absence of H3K27me3 on their promoters. This suggests that a permissive epigenetic landscape allows stress-specific Atf6 target gene expression.

Original languageEnglish (US)
Pages (from-to)107-124
Number of pages18
JournalGenomics
Volume114
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • ATF6
  • Chromatin
  • Epigenome
  • Liver
  • Unfolded Protein response

ASJC Scopus subject areas

  • Genetics

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