Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

Abstract

Transcription factors (TFs) and their combinatorial control on cis-regulatory elements play critical role in the co-expression of genes. This affects the interaction of genes in the transcriptome and thus may affect signals that cascade through cellular pathways. Using a combination of bioinformatic approaches, we sought to identify such common combinations of TFs in a set of ethanol-responsive (ER) genes and assess the role of ethanol in affecting multiple pathways through their co-regulation. Our results show that the metallothionein genes are regulated by TF motifs cAMP responsive element binding protein (CREB) and metal-activated transcription factor 1 and primarily involved in zinc ion homeostasis. We have also identified new target genes, Synaptojanin 1 and tryptophan hydroxylase 1, potentially regulated by this module. Altered arrangement of TF-binding sites in the module may direct the action of these and other target genes in intracellular signaling cascades, cell growth and/or maintenance. In addition to CREB, other key TFs identified are ecotropic viral integration site-1 and SP1. These modulate the contribution of the target ER genes in cell cycle regulation and apoptosis or programmed cell death. Multiple lines of evidence confirm the above findings and indicate that different groups of ER genes are involved in different biological processes and their co-regulation most likely results from different sets of regulatory modules. These findings associate the role of the ER genes studied and their potential TF modules with alcohol response pathways and phenotypes.

Ethanol-Induced Upregulation of 10-Formyltetrahydrofolate Dehydrogenase Helps Relieve Ethanol-Induced Oxidative Stress

“…Sp1 has been reported to regulate a group of "ethanol-responsive genes" (25). Sp1 also participates in the transcriptional regulation of several folate-requiring enzymes, including serine hydroxymethyltransferase (SHMT) and dihydrofolate reductase (DHFR) (24,26,27).…”

Ethanol–BDNF interactions: Still more questions than answers

“…A detailed discussion of region-specific regulation of CREB as it relates to behavioral phenotypes is presented in Section 6 but is introduced here in the context of cellular signaling. An in silico analysis of promoter elements in ethanol responsive genes has identified CREB as a potential mediator of ethanol effects on gene expression (Uddin and Singh 2007). Using mice expressing LacZ under a CRE, an acute exposure to ethanol increased CRE-mediated gene transcription (Asyyed et al, 2007) in NAc, PFC, Septum, BNST, Lateral Habenula, BLA, PVN, hippocampus, VTA and SN, in addition to hypothalamic nuclei.…”

Synchronized genetic activities in Alzheimer’s brains revealed by heterogeneity-capturing network analysis

“…It has been shown that glucocorticoid-induced phosphorylation of CREB is dependent upon serine/threonineprotein kinase, SGK 37 , and SGK3 (aka CISK) is also a member of this module. Conversely, CREB has been implicated in the regulation of SGK3 during apoptosis 38 , and CREB has also been suggested to regulate the following module members: TNFSF15 (aka VEGI), HSD17B7, POLK, IL-18, DUSP19, RSAD2, ICAI (aka ICA69), KLHL28 (aka BTBD5), SLC5A8, and ZNF667 (aka MIPU1).…”