As a potential candidate to generate an everlasting cell source to treat various diseases, embryonic stem cells are regarded as a promising therapeutic tool in the regenerative medicine field. Cohesin, a multi-functional complex that controls various cellular activities, plays roles not only in organizing chromosome dynamics but also in controlling transcriptional activities related to self-renewal and differentiation of stem cells. Here, we report a novel role of the α-kleisin subunits of cohesin (RAD21 and REC8) in the maintenance of the balance between these two stem-cell processes. By knocking down REC8, RAD21, or the non-kleisin cohesin subunit SMC3 in mouse embryonic stem cells, we show that reduction in cohesin level impairs their self-renewal. Interestingly, the transcriptomic analysis revealed that knocking down each cohesin subunit enables the differentiation of embryonic stem cells into specific lineages. Specifically, embryonic stem cells in which cohesin subunit RAD21 were knocked down differentiated into cells expressing neural alongside germline lineage markers. Thus, we conclude that cohesin appears to control the fate determination of embryonic stem cells.
Epigenetic alterations explained by the “loss of heterochromatin” model have been proposed as a universal mechanism of aging, but the region-specific changes of heterochromatin during aging are unclear. Here, we examine age-dependent transcriptomic profiling of mouse retinal neurons to identify epigenetic regulators involved in heterochromatin loss. RNA sequencing analysis revealed gradual down-regulation of Kdm3b during retinal aging. Disruption of Kdm3b (Kdm3b+/-) in 12-month-old mouse retina decreased the number of cone photoreceptors and changed the morphology of cone ribbon synapses. Integration of transcriptome profiling with epigenomic analysis demonstrated gain of heterochromatin feature in synapse assembly and vesicle transport genes via the accumulation of H3K9 mono- and di-methylation. However, the loss of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that this KDM3B-centered epigenomic network is crucial for maintaining cone photoreceptor homeostasis via the modulation of gene-set specific heterochromatin features during aging.
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