Wang, l. | Search bioRxiv

bioRxiv2026

Enhanced Hi-C Capture Analysis reveals complex regulatory architecture at the PICALM-EED locus for Alzheimer Disease

ObjectiveBoth the phosphatidylinositol binding clathrin assembly protein gene (PICALM) and the embryonic ectoderm development gene (EED) have been implicated as causal genes driving a genome-wide association for Alzheimer disease (AD) risk. We employed a new virtual approach using genome-wide chromatin interactions (Hi-C) called enhanced Hi-C Capture Analysis (eHiCA) to identify the genes and regulatory regions that are driving this important AD risk association. MethodsHi-C data from the frontal cortex of eight AD patients, as well as inducible pluripotent stem cell-derived microglia and spheroids of AD and control patients were used. We applied 14 eHiCA baits each containing a GWAS SNP to identify the cis regulatory interactions in this GWAS locus at a 5kb resolution. ResultsThe baits derived from the GWAS associated haplotype primarily interacted with the PICALM promoter and the large cis-regulatory elements cluster (CREe) lying upstream of the EED promoter. The EED promoter interacts with PICALM gene body and promoter region but not directly with the associated risk haplotype. Although the AD-associated variants segregate together as a haplotype in the population, each bait exhibited distinct functional chromatin interactions. InterpretationThe PICALM gene is the primary driver of the association in microglia along with the CREe locus. Different SNPs in a segregating haplotype can display different physical Hi-C interactions. This study demonstrates that eHiCA can help resolve the casual genes driving complex GWAS associations, opening new pathways to study Alzheimer disease and other disorders.

genomics↗

bioRxiv2024

Reduced expression of PER2 protein contrbutes to β1-AA induced cardiac autophagy rhythm disorder

It has been confirmed that heart failure may be linked to fluctuations in autophagy rhythm of cardiomyocytes throughout the day. It is known that circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research has confirmed the presence of {beta}1-Adrenergic receptor autoantibodies ({beta}1-AA) could induce inhibition of myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether {beta}1-AA induces cardiac autophagy rhythm disorder by affecting PER2 expression. This study find that {beta}1-AA disrupts the autophagy rhythm in cardiomyocytes, primarily indicates by the decreased expression of the autophagy marker protein LC3; {beta}1-AA induces disruption of the rhythmic expression of PER2 protein in myocardial cells, mainly manifests by a decrease in PER2 protein expression; Metoprolol is employed to verify that the {beta}1-adrenergic receptor contributes to the reduction of Per2 protein caused by {beta}1-AA. Knocking down Per2 with lentivirus reduces the inhibition of LC3 expression caused by {beta}1-AA, while overexpressing Per2 in cardiomyocytes using lentivirus significantly restores {beta}1-AA-induced decline in LC3 expression. At the same time, mTORC1 activation is found to participate in {beta}1-AA-induced autophagy inhibition of cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, it is confirmed that the decreased expression of PER2 protein caused by {beta}1-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides experimental basis for the precision treatment of cardiovascular diseases from the perspective of biological rhythm.

molecular biology↗