Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Abstract

epilepsy is a widespread neurological disease characterized by abnormal neuronal activity resulting in recurrent seizures. there is mounting evidence that a circadian system disruption, involving clock genes and their downstream transcriptional regulators, is associated with epilepsy. in this study, we characterized the hippocampal expression of clock genes and pAR bZip transcription factors (tfs) in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainic acid (KA). the expression of PAR bZIP TFs was significantly altered following KA injection as well as in other rodent models of acquired epilepsy. Although the PAR bZIP TFs are regulated by proinflammatory cytokines in peripheral tissues, we discovered that the regulation of their expression is inflammation-independent in hippocampal tissue and rather mediated by clock genes and hyperexcitability. furthermore, we report that hepatic leukemia factor (Hlf), a member of pAR bZip tfs family, is invariably downregulated in animal models of acquired epilepsy, regulates neuronal activity in vitro and its overexpression in dentate gyrus neurons in vivo leads to altered expression of genes associated with seizures and epilepsy. overall, our study provides further evidence of pAR bZip tfs involvement in epileptogenesis and points to Hlf as the key player. Epilepsy is a chronic brain disease characterized by the occurrence of recurrent seizures, which are the result of an excessive electrical discharge or hypersynchronization of a group of neurons in distinct areas of the brain. Temporal lobe epilepsy (TLE) is the most common subtype of acquired epilepsy 1. TLE, affecting the hippocampal formation and surrounding cortices of the temporal lobe, is associated with pathological changes including neuroinflammation and neurodegeneration resulting in impaired cognition 2. Recent studies provided converging evidence that the circadian system might be disrupted in epilepsy 3,4. At the molecular level, core clock genes form a transcriptional-translational feedback loop that drives their diurnal oscillations. The positive loop members CLOCK (or NPAS2) and BMAL1 form heterodimers that activate the expression of negative feedback loop members, CRY and PER, by binding to E-box motives in their promoters. CRY and PER consequently inhibit the transcriptional activity of CLOCK/NPAS2:BMAL1 complex and thereby their own expression. The inhibition of BMAL1 expression is additionally mediated in a second negative feedback loop by REV-erb-α and RORC 5,6. Moreover, core clock components interact with the expression of the proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factors (TFs). This family is composed of three activators, DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), TEF (thyrotrophic embryonic factor) and one suppressor of transcription E4 Promoter-Binding Protein 4 (E4BP4), known also as NFIL3 7-10. It has been shown that E4BP4 has an opposite rhythm of oscillation compared to positive members of PAR...

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes

“…Interestingly, global triple KOs (tKOs) of the PAR bZip transcription factors have disrupted xenobiotic efflux in the liver, low circulating endogenous steroids, and low blood pressure (Gachon et al, 2006;Wang et al, 2010). The PAR bZip transcription factors have been further implicated in epilepsy and shown to be modulated by hyperactive neuronal activity, but cell-specific roles have also not yet been explored in this context (Gachon et al, 2004;Rambousek et al, 2020).…”

Predicting the impact of sequence motifs on gene regulation using single-cell data

“…higher weights for Nfib in the lower layers and higher weights for Mef2c in the middle layers, are consistent with previous results based on bulk ATAC-seq from sorted populations 51 . The most notable finding is the Hlf motif ( Fig 6b ) which was not identified by Gray et al Reports linking misregulation of Hlf in the dentate gyrus to epilepsy shows that the gene has important functions in the brain, suggesting that it could be important in the visual cortex as well 52,53 . Interestingly, like many other motifs, Hlf has non-uniform weights across layers ( Fig 6c ).…”

A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex

“…Since Hlf and Tef are progressively upregulated during prolonged TTX treatment, which can lead to subsequent epilepsy (Galvan et al, 2000; Scharfman, 2002), we entertained the hypothesis that they may contribute to the homeostatic increase in network excitability following activity deprivation. On the other hand, loss of function of members of the PAR bZIP family of TFs are also associated with epileptic phenotypes (Hawkins and Kearney, 2012, 2016; Rambousek et al, 2020). Specifically, triple knockout (TKO) Hlf -/- /Dbp -/- / Tef -/- mice have epilepsy (Gachon et al, 2004).…”