Research Focus

The primary focus of our research is to understand the functions of microRNA control and its underlying molecular mechanisms in the mammalian immune system, under health and disease conditions.

MicroRNAs have recently emerged as important factors in the post-transcriptional control of cellular protein concentrations in metazoan organisms. These ~22 nucleotide RNAs pair with mRNAs of protein coding genes to specify their translational repression or degradation. MicroRNAs display distinct temporal and spatial expression patterns and regulate a diverse range of cellular processes, including cell differentiation, proliferation, and apoptosis. Emerging evidence suggests that they can be involved in the control of lymphocyte development and function, as well as lymphomagenesis. However, the specific functions, expression regulation, and molecular mechanisms of action of individual microRNAs remain largely unknown.

We identified a few lymphocyte-specific microRNAs by expression profiling and investigated their functions by generating and analyzing mice with loss- and gain-of-function mutation. We have found that miR-150 controls c-Myb expression and regulates B cell development and response. We also discovered that another microRNA, miR-17~92, contributes to lymphomagenesis by downregulating the protein levels of Pten and Bim. The mice with elevated miR-17~92 expression in their lymphocytes developed lymphoproliferative disease, autoimmunity, and died prematurely.

Based on studies from us and other investigators, some key features of microRNA control have been revealed: (1) a dose-dependent regulation of protein concentrations of target genes over a mostly modest range; (2) subtle changes of concentrations of some key cellular proteins can have profound physiological effects as documented by the many pathologies arising from haploinsufficiency; (3) targeting of several components of a functional network may further enhance the functional impact of microRNA control. A major challenge in the field is to identify the critical targets of individual microRNAs and the molecular pathways they regulate in a given biological context.

We are employing genetic, genomic, proteomic, biochemical, and bioinformatics approaches to understand the functions and molecular mechanisms of microRNA control at molecular, cellular, and system levels, in the context of lymphocyte differentiation, lymphomagenesis and autoimmune diseases. These experimental approaches can also be used to study microRNAs in other systems, when opportunities emerge.

Selected References (Note: * indicates co-first authors.)

  1. Monticelli S*, Ansel KM*, Xiao C*, Socci ND*, Krichevsky AM, Thai TH, Rajewsky N, Marks DS, Sander C, Rajewsky K, Rao A, Kosik KS. (2005) MicroRNA profiling of the murine hematopoietic system. Genome Biology 6(8): R71. PMCID: PMC1273638
  2. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K. (2007) Regulation of the germinal center response by microRNA-155. Science 316: 604-608. PMID: 17463289
  3. Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K. (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131: 146-159. PMID: 17923094
  4. Xiao C*, Srinivasan L*, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K. (2008) Lymphoproliferative disease and autoimmunity in mice with elevated miR-17-92 expression in lymphocytes. Nature Immunology 9:405-14. PMCID: PMC2533767
  5. Xiao C and Rajewsky K. (2009) MicroRNA Control in the Immune System: Basic Principles. Cell 136: 26-36. PMID:19135886
  6. Kang SG*, Liu WH*, Lu P*, Jin HY, Lim HW, Shepherd J, Fremgen D, Verdin E, Oldstone MBA, Qi H, Teijaro JR, Xiao C (2013) MiR-17~92 family microRNAs are critical regulators of T follicular helper cell differentiation. Nature Immunology, 14:849-57. PMID: 23812097
  7. Jin HY*, Oda H*, Lai M*, Skalsky RL, Bethel K, Shepherd J, Kang SG, Liu WH, Sabouri-Ghomi M, Cullen BR, Rajewsky K, Xiao C (2013) MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. The EMBO J., 32:2377-91. PMID: 23921550
  8. Jin HY, Lai M, Xiao C (2014) microRNA-17~92 is a powerful cancer driver and a therapeutic target. Cell Cycle 13:495-6. PMID: 24419145
  9. Jin HY, Xiao C (2015) MicroRNA Mechanisms of Action: What have We Learned from Mice? Front Genet. 6:328. PMID: 26635864
  10. Jin HY*, Gonzalez-Martin A*, Miletic AV, Lai M, Knight S, Sabouri-Ghomi M, Head SR, Macauley MS, Rickert RC, Xiao C (2015) Transfection of microRNA Mimics Should Be Used with Caution. Front Genet. 6:340. PMID: 26697058
  11. Gonzalez-Martin A, Adams BD, Lai M, Shepherd J, Salvador-Bernaldez M, Salvador JM, Lu J, Nemazee D, Xiao C (2016) The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nature Immunology 2016 Feb 22. doi: 10.1038/ni.3385. [Epub ahead of print]