A method of detecting DNase I hypersensitive sites ((DHS) in a single cell or very small number of cells, including cells recovered from formalin-fixed paraffin-embedded (FFPE) tissue slides of patient samples. DHS has revealed a large number of potential regulatory elements for transcriptional regulation in various cell types. The application of DNase-Seq techniques to patient samples can elucidate pathophysiological mechanisms of gene function in a variety of diseases as well as provide potentially important diagnostic and prognostic information. Unfortunately, the current DNase-Seq techniques require large number of cells and are applicable only to larger biopsies and surgical specimens. This technique, called Pico-Seq, allows detection when only very small population of cells are available, such as rare primary tumor cells and circulating-tumor-cells, isolated by a variety of methods. Pico-Seq uses conditions capable of restoring the DNase I sensitivity, similar to native/fresh cells, in tissue/cells from slides processed by extremely harsh conditions, such as in FFPE tissues.