Epigenomic analysis of Alzheimer's disease brains reveals diminished CTCF binding on genes involved in synaptic organization

Epigenetic aberrations are suggested to play an important role in transcriptional alterations in Alzheimer's disease (AD). One of the key mechanisms of epigenetic regulation of gene expression is through the dynamic organization of chromatin structure via the master genome architecture protein, CCCTC-binding factor (CTCF). By forming chromatin loops, CTCF can influence gene transcription in a complex manner. To find out whether genome-wide DNA binding sites for CTCF are altered in AD, we compared CTCF chromatin immunoprecipitation sequencing (ChIP-Seq) data from frontal cortex of human AD patients and normal controls (n=9 pairs, all females). We have revealed that CTCF-binding affinity on many genes is significantly reduced in AD patients, and these genes are enriched in synaptic organization, cell adhesion, and actin cytoskeleton, including synaptic scaffolding molecules and receptors, such as SHANK2, HOMER1, NRXN1, CNTNAP2 and GRIN2A, and protocadherin (PCDH) and cadherin (CDH) family members. By comparing transcriptomic data from AD patients, we have discovered that many of the synaptic and adhesion genes with reduced CTCF binding in AD are significantly reduced in their mRNA expression. Moreover, a significant overlap of genes with the diminished CTCF binding and the reduced H3K27ac is identified in AD, with the common genes enriched in synaptic organization. These data suggest that the CTCF-controlled 3D chromatin organization is perturbed in AD, which may be linked to the diminished expression of target genes, probably through changes in histone modification. Differential analysis of Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for CTCF between "Alzheimer's Disease" and "No cognitive decline" groups from postmortem PFC tissue. BAM files (not uploaded) were generated using bowtie2, BED files were generated using macs2 BigWig files were generated using BamCoverage feature in DeepTools, from BAM files assembly: hg38