Aging-Associated Changes in Cognition, Expression and Epigenetic Regulation of Chondroitin 6-Sulfotransferase Chst3

Abstract

Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related genes in the hippocampus of young, aged and very aged mice. ECM gene expression was downregulated, despite the accumulation of ECM proteoglycans during aging. The most robustly downregulated gene was carbohydrate sulfotransferase 3 (Chst3), the enzyme responsible for the chondroitin 6-sulfation (C6S) of proteoglycans. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of the Chst3 gene, resulting in the downregulation of Chst3 expression in non-neuronal cells. Cluster analysis revealed that the expression of lecticans—substrates of CHST3—is tightly co-regulated with this enzyme. These changes in ECM-related genes were accompanied by an age-confounded decline in cognitive performance. Despite the co-directional impairment in cognitive function and average Chst3 expression in the studied age groups, at the individual level we found a negative correlation between mRNA levels of Chst3 and cognitive performance within the very aged group. An analysis of correlations between the expression of ECM-related genes and cognitive performance in novel object versus novel location recognition tasks revealed an apparent trade-off in the positive gene effects in one task at the expense of another. Further analysis revealed that, despite the reduction in the Chst3 mRNA, the expression of CHST3 protein is increased in glial cells but not in neurons, which, however, does not lead to changes in the absolute level of C6S and even results in the decrease in C6S in perineuronal, perisynaptic and periaxonal ECM relative to the elevated expression of its protein carrier versican.

Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG

“…Besides LAMP1 and LAMP2, other significantly hypoglycosylated proteins included hyaluronan and proteoglycan link protein 1 (HAPLN1) and carbohydrate sulfotransferase 3 (CHST3). Both HAPLN1 and CHST3 are the major components of the extracellular matrix and are involved in cell migration and differentiation [ 54 , 55 ]. Hypoglycosylation of these proteins might reduce their functions that could affect cell growth, and eventually promote cell death.…”

Focal clusters of peri-synaptic matrix contribute to activity-dependent plasticity and memory in mice

“…Our proteomic findings highlight Vcan as one of the main core proteins bearing CS56 glycans. Interestingly, the co-expression of Vcan and CS56-reactive glycans had already been described in the mouse brain, 23 and Vcan was shown to regulate the expression of Chst7 in smooth muscle cells. 46 Hence, we decided to test whether CS56-labeled 6-sulfated chondroitin sulfate and Vcan are functionally related in the brain.…”

“… 10 Specifically, sulfation in position 6 was shown to positively mediate synaptogenesis, enhancing the establishment of synaptic contacts. 11 , 21 – 23 This makes it an ideally suitable molecular player to participate in the dynamic and acute phase of local synaptic remodeling.…”

Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

“…No. E3750) according to the manufacturer's recommendations (Baidoe-Ansah et al, 2022) and products were further checked for genomic DNA contamination by using Nano-drop and gel electrophoresis to measure the RNA yield, purity, and integrity, respectively. Then, 2 μg of RNA was used for cDNA conversion using the High-Capacity cDNA Reverse Transcription Kit (Cat.…”