The field of regulatory genomics has recently witnessed significantly increased interest in the three-dimensional structure of DNA in the nucleus, catalyzed by the availability of Hi-C data sets that characterize chromatin architecture on a genome-wide scale. Systematic analysis of the proximity between genomic regions is crucial for understanding the relationship between genome form and function, which in turn can stimulate the development of therapeutic approaches to a broad range of systemic and infectious human diseases, including cancer and malaria. In this talk, I will present two of my recent projects concerning genome architecture and gene regulation. First, I will talk about our study of the dynamic genome architecture in human malaria parasite (Plasmodium falciparum) which revealed that the parasite has a complex genome architecture shaped around precisely regulating the virulence gene expression and that this architecture goes through holistic changes during its erythrocytic cycle in correlation with overall transcriptional activity. Next, I will present a novel statistical method for assigning confidence estimates to Hi-C data which identifies significant interactions that preferentially link expressed gene promoters to active enhancers in human embryonic stem cells (ESCs), confirms previously validated, cell line-specific contacts in mouse, and links loci with similar replication timing in human and mouse ESCs.