The intestine is one of the fastest regenerative tissues in the body, and homeostasis of the tissue requires robust regulations of intra- and inter-cellular signaling. The stem cells reside at crypt bottom of intestinal epithelium serve as the workhorse of tissue regeneration and keep the tissue homeostasis. When dysregulated events occur to normal intestine cells, cancerous cells often emerge with unchecked cell growth and perturbed cell death, and escape from rigorous mechanisms of cellular signaling regulations. Colorectal cancer (CRC) is one of the most common cause of cancer deaths. Current treatments include surgery and chemotherapy, but disease recurrence occurs frequently. The continuous renewal of intestinal epithelium relies on the presence of intestinal stem cells that could be at the origin of CRC and contribute to therapy resistance and metastases. Several cell signaling pathways and regulatory elements involve in both intestinal cell homeostasis and tumorigenesis. My studies focus on understanding the regulation in intestinal stem cell niche and applying transcriptome and chromatin accessibility profiling to investigate drug resistance in colon cancer. Tissue homeostasis requires rigorous control mechanisms for stem cell division and maintenance of a stable stem cell niche. In the intestinal stem cell (ISC) niche, ISCs and Paneth cells form a stable pattern to control stem cell behavior. However, how is the stem cell niche pattern dynamically regulated and maintained in a rapid regenerative environment still remains unclear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. This study highlights the importance of Notch 1 positive feedback mechanisms in spatiotemporal control of the stem cell niche. Patients with advanced colorectal cancer (CRC) develop chemoresistance to current standard-of-care therapies. We used patient-derived organoids (PDO) from metastatic CRC patients and integrated chromatin and transcriptomic profiling to show that resistant tumor cells remodel their chromatin in response to chemotherapy. Personalized therapy with pharmacological inhibitor of FGFR1 or OXTR, two novel targets for resistant CRC, circumvents oxaliplatin resistance. This study demonstrates the combination of PDO and integrated chromatin/transcriptomic analysis as a potential precision medicine platform to overcome chemoresistance