Research & Initiatives
m6A: from a chemical mark to a therapeutic target
Information in mRNA has primarily been thought to be confined to its nucleotide sequence. However, the advent of mapping techniques has revealed that mRNA contains additional information in the form of chemical modifications. The most abundant modified nucleotide is N6-methyladenosine (m6A), a methyl modification of adenosine. M6A has the well-established function of causing the degradation of modified mRNAs, compared to non-methylated mRNAs.
Importantly, in various cancer types, cells reshape their transcriptome by dysregulating m6A mRNA levels.
Although m6A-mRNA appears highly altered in various cancer types, a major challenge is identifying the mechanisms controlling m6A mRNA dysregulation. Our lab aims to tackle this challenge and uncover fundamental mechanisms that govern m6A mRNA fate in normal and disease states. We employ a multi-disciplinary approach, combining cutting-edge CRISPR-Cas9 base editor screens, massively parallel tethering screen approaches, molecular tagging, and advanced data analyses. The integrated combination of these methodologies will interrogate m6A's contribution to mRNA fate with unprecedented throughput and resolution.
Interrogation of m6A
regulators
m6A contribution to phase-separated compartments
m6A role
in acute myeloid leukemia onset
and hematopoietic cell differentiation
Our work in the field has focused on identifying proteins involved in m6A regulation. Here, we propose identifying the mechanisms modulating these m6A-related proteins to explain how m6A is dysregulated in cancer.
Our work has revealed that m6A mRNA–YTHDF complexes partition into different endogenous phase-separated compartments, such as P-bodies, stress granules, or neuronal RNA granules.
We are interested in dissecting the dynamics of these compartments' assembly by developing innovative single-molecule imaging methods.
One of the clearest examples where m6A deregulation contributes to disease is acute myeloid leukemia (AML). We contributed to seminal publications showing that elevated m6A levels maintain AML cells in a blast-like undifferentiated state.
Our lab is interested in further exploring the contribution of m6A in AML onset.
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