CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons

Abstract

The cyclic AMP response element binding protein (CREB) is a primary hub of activity-driven genetic programs in neurons controlling plasticity, neurogenesis and survival. By contrast, the gene networks coordinated by CREB in astrocytes are unknown despite the fact that the astrocytic CREB is also activity-driven and neuroprotective. Herein we identified the transcriptional programs regulated by CREB in astrocytes as compared to neurons using, as study materials, transcriptome databases of astrocyte exposed to well-known activators of CREB-dependent transcription as well as publicly available transcriptomes of neuronal cultures. Functional CREB signatures were extracted from the transcriptomes using Gene Ontology, adult-brain gene lists generated by Translating Ribosome Affinity Purification (TRAP) and CREB-target gene repositories. We found minimal overlap between CREB signatures in astrocytes and neurons. In astrocytes, the top triad of functions regulated by CREB consists of ‘Gene expression’, ‘Mitochondria’, and ‘Signalling’, while in neurons it is ‘Neurotransmission’, ‘Signalling’ and ‘Gene expression’, the latter two being represented by different genes from those in astrocytes. The newly generated databases will provide a tool to explore novel means whereby CREB impinges on brain functions requiring adaptive, long-lasting changes by coordinating transcriptional cascades in astrocytes.

Early alteration of epigenetic-related transcription in Huntington’s disease mouse models

“…S1b ); GSE19402 for Camk2a-cre; Ehmt2 fl/fl and Camk2a-cre; Ehmt1 fl/fl 42 ; GSE22969 for Kat6b gt/gt 47 ; GSE30880 for Crebbp + /− 50 ; GSE38218, GSE38219 for Hdac4 + /− 49 ; GSE42987 for Mecp2 −/y , Mecp2 −/y ; R270X Tg and Mecp2 −/y ; G273X Tg 45 ; GSE44868 for acute TSA treatment 46 ; GSE48437 for CaMKII-tTA; tetO-HIST1H2BJ/GFP ) 44 ; GSE84243 for Ezh1 −/− ; Camk2a-cre; Ezh2 fl/fl 43 ; and GSE90836 for Kmt2d + /βGeo 48 (Figs 4 and S2 ). As in previous studies 84 – 86 , the distribution of the top DRG was plotted across the whole transcriptome of reference, once ranked by the t statistics retrieved in the differential expression analysis, and divided into bins of equal number of genes.…”

Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory

“…CREB can control many genes in the glycolytic pathway in astrocytes and its constitutive activation up-regulates the capacity of astrocytes to utilise glucose [ 73 ]. Since CREB in neurons controls PGC-1α and other neuroprotective genes like Bdnf and Bcl2 , stimulation of CREB activity in the brain may have protective effects at multiple levels acting via multiple cell types [ 75 ]. There is emerging evidence that other transcription factors in astrocytes also regulate important homeostatic processes relevant to neurodegenerative disease and are the topic of ongoing investigation.…”

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…Another widely used approach for the identification of genes downstream of CREB, or involved in learning, is transcriptomics, in particular microarrays (Figure ). In mammals, both cell cultures and dissected brain regions have been used to analyze the transcriptomic profile after stimulation of CREB. A variety of stimuli have been used to activate the CREB signaling pathway, for example, forskolin treatment, which activates cAMP‐signaling, constitutive active CREB, electrostimulation, or conditioning training .…”

“…In mammals, both cell cultures and dissected brain regions have been used to analyze the transcriptomic profile after stimulation of CREB. A variety of stimuli have been used to activate the CREB signaling pathway, for example, forskolin treatment, which activates cAMP‐signaling, constitutive active CREB, electrostimulation, or conditioning training . Similar approaches have also been used in Drosophila , Aplysia , and C. elegans .…”