SRP404879 PRJNA894996 GSE216694 Reorganization of H3K9me heterochromatin leads the neuronal impairment via the cascading destruction of KDM3B-centered epigenomic network Histone H3K9 methylated heterochromatin silences repetitive non-coding sequences and lineage-specific genes during development, but how tissue-specific genes escape from heterochromatin in differentiated cells is unclear. Here, we examine age-dependent transcriptomic profiling of terminally differentiated mouse retina to identify epigenetic regulators involved in heterochromatin reorganization. The single-cell RNA sequencing analysis reveal a gradual downregulation of Kdm3b in cone photoreceptors during aging. Disruption of Kdm3b (Kdm3b+/-) of 12-month-old mouse retina leads to the decreasing number of cones via apoptosis, and it changes the morphology of cone ribbon synapses. Integration of transcriptome with epigenomic analysis in Kdm3b+/- retinas demonstrate gains of heterochromatin feature in synapse assembly and vesicle transport genes that are downregulated via the accumulation of H3K9me1/2. Contrary, losses of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that KDM3B-centered epigenomic network is crucial for balancing of cone photoreceptor homeostasis via the modulation of gene-set specific heterochromatin features during aging. Overall design: We compared gene expression profiles between mouse retina of wild type and Kdm3b heterozygous. ChIP-seq for H3K9me1, H3K9me2 and H3K9me3 were performed in mouse retina between wild type and heterozygous. GSE216694 pubmed 39165843