Cancer Research UK Senior Fellow
Stem cells are established during development and remain present in adulthood allowing the body to replace, restore and regenerate dead, damaged or diseased cells. Stem cells continuously maintain their population (self-renewal) while generating progeny (differentiation). During self-renewal stem cells have to avoid cell cycle exit and differentiation; whereas during differentiation stem cells must evade uncontrolled proliferation. Dissecting the regulatory pathways controlling the balance between these two states is fundamental to understanding how stem cell mis-regulation causes human diseases and cancer.
While transcriptional regulation of stem cells is increasingly understood, virtually nothing is known about how post-transcriptional mechanisms can influence stem cell maintenance. Post-transcriptional modifications are commonly found in non-coding RNA species and our recent studies identified cytosine-5 methylation (m5C) of RNA as a novel mechanism regulating stem cell fate.
To dissect the cellular and molecular functions of cytosine-5 methylated RNA, we are using a combination of system-wide approaches, mouse models and in vitro differentiation assays. Our comprehensive approach will answer how post-transcriptional modification controls stem cell fate in normal tissues and how aberrant cytosine-5 methylation pathways can cause human diseases including cancer.
Aberrant methylation of tRNAs links cellular stress to neuro-developmental diseases, EMBO J, 33: 2020-39
Hussain S, Sajini AA, Blanco S, Dietmann S, Lombard P, Sugimoto Y, Paramor M, Gleeson JG, Odom DT, Ule J, Frye M, (2013), NSun2-mediated cytosine-5 methylation of Vault non-coding RNA determines its processing into regulatory small RNAs, Cell Reports, 4:255-61
Hussain S, Tuorto F, Menon S, Blanco S, Watt S, Kudo NR, Lyko F, Frye M, (2013), The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation, Mol. Cell Biol, 33:1561-70
Driskell I, Oda H, Blanco S, Nascimento EM, Humphreys P, Frye M, (2011), The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin, EMBO J, 31:616-29
Nascimento EM, Cox CL, MacArthur S, Hussain S, Trotter M, Blanco S, Menon S, Nichols J, Kübler B, Aznar Benitah S, Hendrich B, Odom DT, Frye M, (2011), The opposing transcriptional functions of Sin3A and c-Myc are required to maintain tissue homeostasis, Nature Cell Biology, 13:1395-405
Blanco S, Kurowski A, Nichols J, Watt FM, Aznar Benitah S, Frye M, (2011), The RNA methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate, PLoS Genetics, 7:e1002403
Hussain S, Benavente SB, Nascimento E, Dragoni I, Kurowski A, Gillich A, Humphreys P, Frye M, (2009), The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability, J Cell Biol, 186:27-40
Frye M, Watt FM, (2006), The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors, Curr Biol, 16:971-81