NO. 50

CIMR Wednesday Lecture Series

Time:

Wednesday, Dec. 04 2024, 4:00 p.m.

Location:

Yifu Lecture Hall, North Basic Research Building 

Host：

Zihou Deng (邓子厚)

Chinese Institutes for Medical Research, Beijing

Speaker：

Yuanming Cheng (程远明)

Principal Investigator

Institute of Modern Biology, Nanjing University

TITLE：

RNA Epigenetic Regulation in Normal and Malignant Hematopoiesis

ABSTRACT:

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is important for gene expression regulation. Here, a series of our studies indicated the essential role of m6A in normal and malignant hematopoiesis. Depletion of the m6A-forming enzyme METTL3 in human acute myeloid leukemia cells (AML) impairs cell proliferation and delays leukemia progression both in vitro and in vivo. Loss of METTL3 inhibits the translation of c-MYC, BCL2 and PTEN mRNAs and induces phosphorylated AKT, which contributes to the defects upon METTL3 depletion. Furthermore, we found that nuclear m6A reader YTHDC1 undergo liquid-liquid phase separation by binding to m6A RNA and form nuclear YTHDC1- m6A condensates (nYACs). nYACs enable YTHDC1 to protect m6A-mRNAs from exosome-associated RNA degradation and are required for AML cells to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Overall, these results provide a rationale for the therapeutic targeting of m6A in myeloid leukemia. Moreover, by single cell RNA-seq, our results also indicate that RNA methylation controls symmetric commitment and cell identity of HSCs in normal hematopoiesis and provide a general mechanism for how stem cells regulate differentiation fate choice.

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