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. 2015 Dec 14;8:55.
doi: 10.1186/s13072-015-0043-3. eCollection 2015.

Remodeling of Retrotransposon Elements During Epigenetic Induction of Adult Visual Cortical Plasticity by HDAC Inhibitors

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Free PMC article

Remodeling of Retrotransposon Elements During Epigenetic Induction of Adult Visual Cortical Plasticity by HDAC Inhibitors

Andreas Lennartsson et al. Epigenetics Chromatin. .
Free PMC article

Abstract

Background: The capacity for plasticity in the adult brain is limited by the anatomical traces laid down during early postnatal life. Removing certain molecular brakes, such as histone deacetylases (HDACs), has proven to be effective in recapitulating juvenile plasticity in the mature visual cortex (V1). We investigated the chromatin structure and transcriptional control by genome-wide sequencing of DNase I hypersensitive sites (DHSS) and cap analysis of gene expression (CAGE) libraries after HDAC inhibition by valproic acid (VPA) in adult V1.

Results: We found that VPA reliably reactivates the critical period plasticity and induces a dramatic change of chromatin organization in V1 yielding significantly greater accessibility distant from promoters, including at enhancer regions. VPA also induces nucleosome eviction specifically from retrotransposon (in particular SINE) elements. The transiently accessible SINE elements overlap with transcription factor-binding sites of the Fox family. Mapping of transcription start site activity using CAGE revealed transcription of epigenetic and neural plasticity-regulating genes following VPA treatment, which may help to re-program the genomic landscape and reactivate plasticity in the adult cortex.

Conclusions: Treatment with HDAC inhibitors increases accessibility to enhancers and repetitive elements underlying brain-specific gene expression and reactivation of visual cortical plasticity.

Keywords: Chromatin; DHSS; Enhancers; HDAC inhibitors; Retrotransposon elements; Visual cortex plasticity.

Figures

Fig. 1
Fig. 1
VPA reinstates ocular dominance plasticity in adult visual cortex. a The mouse visual system is naturally skewed toward the contralateral eye. Unlike during the CP [32], brief monocular deprivation (4d MD) fails to alter this ocular dominance of V1 neurons rated on a seven-point scale (white bars). b Upon VPA administration (6d) prior to and concurrent with adult MD, responsiveness once again can shift in favor of the open eye (black bars; n = 98 and 103 cells from n = 4 mice per group, CBI = 0.72 and 0.51, respectively; p < 0.001, χ 2 test). c Significant CBI reduction by MD occurs only with VPA (closed circles, p = 0.0002, unpaired two tailed t test versus vehicle, open circles). Enhancing inhibition, an alternative consequence of VPA treatment [33], is insufficient to induce adult plasticity, as benzodiazepine agonists (DZ, closed triangles; Veh, open triangles) fail to reduce CBI. d Reduction of histone deacetylase (HDAC) activity within 2 h of either valproic acid (VPA) or trichostatin A (TSA) administration. HDAC activity normalized to vehicle (***p = 0.0004, **p = 0.0024; unpaired two-tailed t test, n = 3 per group). e Treatment with HDACi re-activates the critical period in adult mice
Fig. 2
Fig. 2
Distribution of DHSS in VPA- or vehicle-treated visual cortex. a Average DHSS tag enrichment around CAGE promoters from a previous study [31] from vehicle (Veh, solid line) and VPA-treated visual cortex (dotted line). Average TPM (tags per million) are computed in 500 bp bins centered around the TSS. Promoters located on chrM are excluded, as are promoters containing a bin with average TPM higher than 10 times the average TPM for that bin across all promoters. b Venn diagram showing the distribution of DHSS tags. c Validation of DHSS by qPCR. DNase I digested DNA from VPA- or vehicle-treated visual cortex were amplified with primer pairs annealing within induced DHSS proximal or distal to CAGE TSS clusters, or randomly in the genome. Data from two biological replicates for each treatment condition is shown (VPA 1 and 2, Veh 1 and 2). Error bars are standard deviations. d Genomic distribution of DHSS clusters with respect to RefSeq gene models
Fig. 3
Fig. 3
VPA-induced expression measured with CAGE. a Overlap between VPA-induced and non-induced TSS clusters (see main text for cluster definition) and RefSeq promoter regions. Promoter regions were defined as the region starting from 1 kb upstream of the RefSeq TSS and ending at the start of the coding region. b Overlap between VPA- and non-induced TSS clusters and previously identified CAGE promoters preferentially expressed in visual or somatosensory cortex. c Distributions (box plots) of the ratio of CAGE tags mapping to the first exon in the VPA- and non-induced samples). Ratios were computed by dividing the number of CAGE tags mapping to the first exon with the number of tags mapping anywhere along the length of the whole gene (including introns) in all genes with at least 10 CAGE tags mapping to the gene. d Selected gene ontology terms for RefSeq genes overlapping tss clusters (overlap definition as in A). VPA-induced and non-induced TSS clusters were analyzed separately using GOStat [42], the full list of significant terms is listed in Additional file 4: Table S3. e Overlap between RefSeq genes overlapping TSS clusters according to the definition in A, and a list of selected VPA induced genes associated with brain development and chromatin regulation. The intersecting genes have alternative promoters that respond differentially to VPA induction. The full list of genes is listed in Additional file 3: Table S2 along with TSS clusters. f Distributions (density plots) of the distance between VPA-induced (VPA-i) and non-induced (non-i) TSS clusters and the closest DHSS
Fig. 4
Fig. 4
VPA induces DHSS at retrotransposon elements. a Genomic distribution of DHSS with respect to repeat regions (defined by RepeatMasker [http://www.repeatmasker.org]). In cases where the same DHSS overlapped several repeats, the overlap with the greatest length was chosen. b Genomic distribution of SINEs overlapping non-induced (non-i) DHSS (leftmost bar), VPA-induced (VPA-i) DHSS (mid bar), and all SINEs (rightmost bar), with respect to RefSeq gene models. c Over-representation of forkhead motifs in induced SINE DHSS compared to all other DHSS. For each JASPAR forkhead motif, the number of matches (obtained using the TFBS toolkit) with at least 80 % similarity were compared between the two groups using one-tailed Wilcoxon rank-sum test. In all cases, p < 1.5e−16. d Overlap between SINEs and Foxa2 binding sites in mouse liver. “non-induced (non-i)/VPA-induced (VPA-i) SINEs” indicates DHSS clusters that overlap SINEs, and “non-induced/induced n.o. SINEs” indicates clusters that do not overlap SINEs. “Top 50 VPA SINEs/n.o. SINEs” indicates the 50 VPA DHSS clusters with highest DHSS tag count in the VPA-i sample, which do or do not overlap SINEs, respectively. e Genome browser view of the 3′ end of the Hectd1 gene (NM_144788), indicating an overlap between VPA DHSS, SINEs and Foxa2 binding sites

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