HOTAIR-YTHDF3 interaction in promoting breast cancer cell metastasis [ATAC-seq]

Long noncoding RNA HOTAIR (HOX antisense intergenic RNA) is an important regulator of breast cancer metastasis. Studies showed that HOTAIR reprograms chromatin state through interacting with Polycomb Repressive Complex 2 (PRC2) to promote breast cancer metastasis. However, it is unclear if there exist other HOTAIR-binding factors which participate in promoting breast cancer metastasis. In the current study, we utilized mass spectrometry (ChIRP-MS) to comprehensively identify RNA-binding proteins (RBPs) associated with HOTAIR. We also performed a high-throughput CRISPR screen to investigate HOTAIR-interacting proteins involved in cell metastasis. We found that many m6A-reader proteins were involved in this progress, including YTHDF3, which is a newly identified HOTAIR partner. We further demonstrated that HOTAIR and YTHDF3 co-regulated the expression of several metastasis-associated genes by modifying their chromatin accessibility in breast cancer cells. Altogether, our work detailed the functional interactome of HOTAIR involved in promoting breast cancer cell metastasis, and suggested a mechanism whereby HOTAIR regulates chromatin state in cooperation with the m6A-reader YTHDF3.