The development of next-generation sequencing has brought a comprehensive understanding of human genome to us. It has been well undertand that human genes are not consecutive but contains numerous cis-regulatory elements. These cis-regulatory elements was proved to be crucial for lineage-specific gene expression during development. To elucidate the gene-regula tory interactome is important not only in understanding the development of human and other spe cies but also provide crucial guidance on studying diseases. This task is surprisingly difficult as cis-regulatory elements can regulate genes that are not their immediate neighbors. Some ele ments could modulate gene expression from a large genome distance. Thus, to uncover the mys tery of gene regulation requires a better understanding of how chromatin fibers folded in 3D among different cell type. Moreover, epigenetic markers emerge to be proven as important indi cators for gene regulation. Recent years have seen rapid progress in technologies for genome wide analysis of 3D genome organization. However, there remains largely unknown between chromatin structure and gene regulation. In addition, lacking high resolution chromatin contacts maps also limit our understanding of mechanism of chromatin folding.To meet the requirement, two major strategies are designed and will be discussed in the thesis. The Chemical-crosslinking Assisted Proximity Capture (CAP-C) strategy improves the chromatin contact maps at high resolution by capture more short range-chromatin contacts. Us ing this strategy, we also discovered an inexplicable relationship between chromatin structure and transcription and proposed that organization of genome may not be a determinant of tran scription but also a consequence of its function. The Nano-hmC-Seal strategy enable us to profile 5hmC location with limited materials. We have successifully utilize this method in studying AML and predict its clinical outcome