34 / 2024-09-29 10:35:49

Nucleolar phase separation regulates nucleolus-associating domain for drug resistance in colorectal cancer

phase separation, genome organization, NAD

Phase separation can regulate genome organization for cell fate determination. However, how this mechanism works in cancer remains to be illustrated. The RNA binding protein, CELF1, is often overexpressed in colorectal cancer (CRC), which contributes to a poor survival in this malignant cancer. Here, we observe that CELF1 can form phase-separated condensates both in vitro and in CRC cells. Moreover, LF1 condensates are localized in the DFC layer of nucleolus, which facilitates rRNA spicing. Loss of CELF1 improves the clarity of nucleolus in nucleus. Furthermore, nucleolus Hi-C (nHi-C) is employed to identified the nucleolus-associating domain (NAD) in CRC cells, and the alteration of NAD in response to CELF1 loss. We find that loss of CELF1 reorganizes NAD, which activates Tet1 by excluding the gene from CRC NAD. Tet1 activation attenuates DNA methylation level and improves Oxaliplatin sensitivity. Taken together, this work depicts a new insight how phase separation of cancer-related proteins contributes to cancer through nucleolar genome reorganization.