Myeloma Genomics and Microenvironment and immune profiling

Category: Myeloma Genomics and Microenvironment and immune profiling

Crosstalk Between m6A and H3K27ac via the YTHDC1-EP300 Feedback Loop Promotes Myelomagenesis

(PA-277) Crosstalk Between m6A and H3K27ac via the YTHDC1-EP300 Feedback Loop Promotes Myelomagenesis

Wednesday, September 17, 2025

Yifan Hou, MD

MD
Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University

Introduction: Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal plasma cell infiltration of the bone marrow and secretion of monoclonal immunoglobulins. In addition to genetic abnormalities and tumor-microenvironment interactions, epigenetic dysregulation has emerged as a key player in MM pathogenesis. Among these, N⁶-methyladenosine (m⁶A), the most abundant internal RNA modification, regulates RNA metabolism through the dynamic interplay of writer, eraser, and reader proteins. Aberrant expression of m⁶A modifiers is frequently observed in cancer and exerts either oncogenic or tumor-suppressive effects in a cancer type-dependent manner. However, the precise roles and mechanisms of m⁶A modifiers in myelomagenesis remain unclear.

Methods: We conducted a series of in vitro and in vivo experiments, including cell culture, primary MM cell isolation, lentiviral transfection, CCK-8 assays, colony formation assays, flow cytometry, xenograft models, RT-qPCR, Western blotting, and RNA decay assays. Multi-omics analyses, including RNA-seq, RIP-seq, MeRIP-seq, ChIP-seq, and ATAC-seq, were also performed.

Results: We identified that the m⁶A reader protein YTHDC1 plays a critical role in myelomagenesis. YTHDC1 is significantly overexpressed in MM cells compared to normal cells from healthy donors, and its elevated expression correlates with poor prognosis. Functional experiments in vitro and in vivo demonstrated that YTHDC1 promotes MM cell proliferation, regulates cell cycle progression, and modulates DNA damage repair in an m⁶A-dependent manner. Through integrative analyses of transcriptomic profiling, YTHDC1 RIP-seq, m⁶A MeRIP-seq, and MM patient cohort data, we identified EP300, which encodes the histone acetyltransferase p300, as a direct downstream target of YTHDC1. Mechanistically, YTHDC1 recognizes and binds to m⁶A-modified EP300 mRNA, enhancing its stability and promoting its overexpression in MM cells. Furthermore, p300 functions as a histone acetyltransferase and transcriptional coactivator, enhancing YTHDC1 transcription by mediating H3K27ac and recruiting TFs of IRF3 and IRF4 to the YTHDC1 promoter. These findings suggest a positive feedback loop between YTHDC1 and EP300, in which epitranscriptomic and epigenetic mechanisms cooperate to drive MM development.

Conclusions: This study explored the crosstalk between RNA m⁶A and histone H3K27ac in MM, proposing a novel positive feedback loop between YTHDC1 and EP300 that promotes myelomagenesis, highlighting the YTHDC1-EP300 axis as a promising target for therapeutic intervention.