SEARCH FOR ARE REGULATORY SEQUENCES IN GENES of MASTER REGULATORS OF autophagy and LYSOSOMAL BIOGENESIS TFEB AND TFE3

Abstract

Transcription factors TFEB and TFE3 are the master regulators of lysosomal biogenesis and autophagy and control most of the protein genes involved in the formation of lysosomes by interacting with the promoters of these genes containing the regulatory motif CLEAR. Their activation is strictly regulated and occurs in response to the violation of lysosomal homeostasis and cell damage. Such effects are accompanied by activation of redox processes and by induction of the redox-sensitive signal system Keap1/Nrf2/ARE, the main purpose of which is to maintain internal homeostasis in apoptosis-inducing, carcinogenic and stressful influences. Thus, the question arises about the existence of regulatory loops between the Keap1/Nrf2/ARE and TFEB(TFE3)/CLEAR signaling systems. To search for the ARE sequence in the TFEB and TFE3 genes, a position frequency matrix was generated based on the 57 functional ARE sequences described in the literature. ARE-like sequences were labeled in the UCSC genome browser for analysis of evolutionary conservation, colocalization with various functional DNA and chromatin modifications, as well as with other regulatory elements. In the human TFEB gene, 15 ARE-like motifs were found. Of these, the sequence located in the first intron is conserved across vertebrates. In the mouse Tfeb gene, 15 ARE-like motifs were also found; one of them is conserved, but is located in the coding exon. Human and mouse transcription factor TFE3 genes contain less ARE-like sequences, among them the sequence conserved across vertebrate is noteworthy, which is located in the second intron. Using the ChIP-seq data from the ENCODE database, the histone landscape in the respective regions of the genome was analyzed and it was established that the evolutionarily conserved ARE regulatory element located in the TFE3 enhancer region likely play a functional role.