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Background:High-order chromatin structure has been shown to play a vital role in gene regulation.Previously we identified two types of sequence domains,CGI(CpG island)forest and CGI prairie,which tend to spatially segregate,but to different extent in different tissues.Here we aim to further quantify the association of domain segregation with gene regulation and therefore differentiation.Methods:By means of the published RNA-seq and Hi-C data,we identified tissue-specific genes and quantitatively investigated how their regulation is relevant to chromatin structure.Besides,two types of gene networks were constructed and the association between gene pair co-regulation and genome organization is discussed.Results:We show that compared to forests,tissue-specific genes tend to be enriched in prairies.Highly specific genes also tend to cluster according to their functions in a relatively small number of prairies.Furthermore,tissue-specific forest-prairie contact formation was associated with the regulation of tissue-specific genes,in particular those in the prairie domains,pointing to the important role of gene positioning,in the linear DNA sequence as well as in 3D chromatin structure,in gene regulatory network formation.Conclusion:We investigated how gene regulation is related to genome organization from the perspective of forest-prairie spatial interactions.Since unlike compartments A and B,forest and prairie are identified solely based on sequence properties.Therefore,the simple and uniform framework(forest-prairie domain segregation)provided here can be utilized to further understand the chromatin structure changes as well as the underlying biological significances in different stages,such as tumorgenesis.