Substantial evidence has accumulated linking epigenome change to alterations in stem cell function during postnatal development and aging. Yet much remains to be learned about causal relationships, and large gaps remain in our understanding of epigenome-transcriptome interactions. Here we investigate structural features of large histone H3K27me3-enriched regions in human stem cell-like monocytes and their dendritic cell derivatives, where the H3K27me3 modification is considered to demarcate Polycomb (PcG) domains. Both differentiation- and postnatal development-related change are explored, initially by confirming expected reciprocal relationships between transcript abundance and span of PcG domains overlapping transcribed regions. PcG-associated postnatal transcriptome change specific to the stem cell-like monocytes is found to be incompletely explained by conventional measures of PcG region structure. To address this, we introduce algorithms that quantify local nucleosome-scale conservation of PcG-region topology. It is shown that topology-based comparisons can reveal broad statistical linkage between postnatal gene down-regulation and epigenome remodeling; further, such comparisons provide access to a previously unexplored dimension of epigenome architecture.