Project 1: Coordination of modifications across RNA species in translation regulation in cancer

Despite modifications occurring in multiple RNA species concurrently, the research field historically has focused on the function of one modification in one RNA species at a time. Since the inception of my laboratory in 2018, I have asked a new question: whether and how modifications across RNA species synergistically influence gene expression. My lab’s work demonstrated, for the first time, that crosstalk between RNA-modifying enzymes influences both the deposition and consequences of several RNA modifications. Specifically, we discovered that the level of tRNA modification is concurrently regulated with mRNA modification via the physical and mechanical interaction of the respective modifying enzymes. Our work provided the first holistic view of modifications across distinct RNA types through a concerted investigation of how the enzyme-mediated methylations collectively impact gene expression and provided a new direction in the pathological mechanisms of dysregulated RNA methylations in cancer.

a.   Ontiveros RJ, Shen H, Stoute J, Yanas A, Cui Y, Zhang Y, and Liu KF*. Coordination of mRNA and tRNA methylations by TRMT10A. Proc. Natl. Acad. Sci. U.S.A., (Direct Submission), 2020, 117(14), 7782-7791. (PMC7149399)

b.   Chen Y, Owens M, Liu KF*. Coordination of RNA modifications in the brain and beyond. Mol. Psych., 28, 2737–2749 (2023) (Invited review)

c.   Owens MC, Zhang C, and Liu KF*. Recent technical advances in the study of nucleic acid modifications. Mol. Cell, 81(20), 4114-4136 (PMC9109655). (Invited review)

d.   Liu F, Clark W, Luo G, Wang XY, Fu Y, Wei J, Wang X, Hao Z, Dai Q, Zheng G, Ma H, Han D, Evans M, Klungland A, Pan T, and He C. ALKBH1-mediated tRNA demethylation regulates translation. Cell, 2016, 167(3), 816-828 [PMC5119773]

Project 2: Understanding the Y chromosome and X-Y paired proteins in sex bias of human cancers

My lab studies how sex chromosome-encoded RNA regulatory proteins differentially influence gene regulation and may explain the sex bias of human cancers. Sex differences are evident in tumor incidence and mortality worldwide, across a wide age range, and in many different cancers. One of the significant keys to sex-biased differences lies in the sex chromosomes. In my laboratory, my students and I have begun investigating whether and how the differences between these X-Y paired protein homologs contribute to sex bias in cancers in non-reproductive tissues. In our most recent publications, my lab demonstrated that DDX3X and DDX3Y (one pair of the X-Y paired proteins) significantly differ in translation regulation, which may lead to sex bias in cancer and neurological disorders. This work, for the first time, systematically reveals the biochemical, biophysical, and cellular functions of a representative X-Y pair of homologs. Our ongoing research expands our discoveries on DDX3X and DDX3Y to more broadly investigate other sex chromosome-encoded homologous proteins and sex chromosome rearrangement in human cancers.

a.  Shen H, Yanas A, Owens M, Zhang C, Fritsch C, Fare CM, Copley KE, Shorter J, Goldman, YE, Liu KF*. Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation. Mol. Cell, (2022), 82, 1 – 16. (PMC9308757)

b.   Yanas A, Him S, Owens M, Liu KF*, Goldman Y*. DDX3X and DDX3Y constitutively form nanometer-scale RNA-protein clusters that foster enzymatic activity. Curr. Biol., (2024) (doi.org/10.1016/j.cub.2024.10.055)

c.   Owens M, Shen H, Yanas A, Mendoza-Figueroa M, Lavorando E, Wei XY, Him S, Tang HY, and Goldman Y*, Liu KF*. Specific catalytically impaired DDX3X mutants form sexually dimorphic hollow condensates. Nat. Commun., (2024) (doi: 10.1038/s41467-024-53636-0)

d.   Owens M, Yanas A, Liu KF*. Sex chromosome-encoded protein homologs: current progress and open questions. Nat. Struct. Mol. Biol., (2024) (DOI: 10.1038/s41594-024-01362-y)

Project 3: Catalytic and non-catalytic functions of rRNA-modifying enzymes

My lab has also studied ribosome biogenesis and function, focusing on ribosome RNA’s catalytic and non-catalytic functions (rRNA)-modifying enzymes in translation regulation. Ribosomes play a central role in translating genetic information for protein synthesis. Each ribosome is a gigantic RNA protein complex consisting of four ribosomal RNAs (rRNA) and approximately 200 indispensable protein assembly and structural factors. What is known from decades of studies is that some ribosome assembly factors also catalyze chemical modifications at more than 200 sites in rRNAs. These rRNA modifications are evolutionarily conserved at high occupancies at the modified sites. However, the consequence of many of those modifications remains largely obscure. Intriguingly, some rRNA modifications are often dispensable for ribosome assembly and cell viability but indispensable for expressing specific sets of genes and protein synthesis. Thus, it has become increasingly appreciated that the ribosome assembly factors play many roles in ribosome assembly and functions.  Furthermore, dysregulation of rRNA-modifying enzymes is frequently seen in human hematopoietic disorders. In the past, the catalytic function of rRNA-modifying enzymes in human hematopoiesis’ physiological and pathological processes was limited. My lab has begun to reveal the function of catalytic and non-catalytic roles of rRNA-modifying enzymes in hematopoietic diseases. The understanding we will gain can be broadly applied to hematopoietic studies and many other biological disciplines.

a.   Gonskikh Y, Stoute J, Shen H, Budinich K, Pingul B, Schultz K, Elashal H, Marmorstein R, Shi J, Liu KF*. Non-catalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia. Genes & Dev., (2023), 37: 321-335 (PMC10153457)

b.   Shen H, Stoute J, and Liu KF*. Structural and catalytic roles of the human 18S rRNA methyltransferases DIMT1 in ribosome assembly and translation. J. Biol. Chem., (2020), 295: 12058-12070 (PMC7443495)

c.   Gonskikh Y, Tirrito C, Bommisetti, P, Mendoza M; Stoute, J, Kim, J, Wang, Q, Song, Y*, Liu KF*. Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function. Nucleic Acids Res., (2024) (doi.org/10.1093/nar/gkae1169)

d.   Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, and Liu KF*. TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J. Biol. Chem., (2021), 296: 100087 (PMC7949041)