Zissimos Mourelatos, M.D.
Associate Professor
Vice-Chair, Neuropathology
Department of Pathology & Laboratory Medicine

Genetics and Gene Regulation Program

Address

613B Stellar Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104-6100

Office tel.: 215-746-0014
Lab tel.: 215-746-0013
Fax: 215-898-9969
E-mail: mourelaz@uphs.upenn.edu

Education

Aristotelian University of Thessaloniki (Greece): M.D., 1991

Research Interests

• Characterization of microRNP assembly and function
• Biogenesis and function of piwi-associated RNAs
• microRNAs and microRNPs in human diseases
  

Key words: MicroRNA, miRNA, microRNP, miRNP, RNA interference, RNAi, RNA Induced Silencing Complex, RISC, short interfering RNAs, siRNA, Argonaute, eIF2C2, posttranscriptional RNA processing, gene silencing, mRNA turnover, translational repression, Fragile X Mental Retardation Protein, FMRP, SMN complex.

Description of Research

A new paradigm of gene expression regulation has emerged recently with the discovery of microRNAs (miRNAs), an evolutionary conserved class of small (~22 nucleotide -nt-), regulatory RNAs. miRNAs bind to Argonaute proteins and typically associate with additional proteins to form microRibonucleoproteins (miRNPs), the effector complexes that mediate translational repression or endonucleolytic cleavage of their cognate mRNAs. Another class of ~22nt RNAs, termed short interfering RNAs (siRNAs), is inextricably linked to miRNA. siRNAs are the effector RNAs that mediate RNA interference (RNAi), are also bound to Argonaute proteins and may assemble with additional proteins; to form complexes termed RNA-Induced Silencing Complexes (RISCs). miRNPs and RISCs are functionally equivalent. siRNAs may also silence chromatin. A working model of the biogenesis and function of miRNAs and siRNAs is presented in Figure 1.

Figure 1. Proposed unified model of mi/siRNA biogenesis and functions

miRNA biogenesis (left): Transcription of endogenous miRNA genes (most likely by RNA polymerase II) generates pri-miRNAs that are processed by Drosha (light pink) in the nucleus into pre-miRNAs. pre-miRNAs are exported to the cytoplasm by exportin-5 (brown) and are processed by Dicer (grey), possibly in conjunction with Argonaute proteins (blue), into "siRNA duplexes" that are unwound by an unknown helicase (yellow) into single stranded mature miRNAs (shown in red). miRNAs bind to Argonaute proteins to form miRgonaute ribonucleoproteins and also associate with additional proteins to form RISCs/miRNPs. In plants, miRNAs are processed in the nucleus.

siRNA biogenesis (right): RNAs derived from transgenes, transposons and heterochromatic repeats are substrates for RNA-dependent RNA polymerase (RdRP) and are converted to dsRNA, which is processed by Dicer into siRNA duplexes. Other Dicer substrates may include exogenous dsRNA (i.e. experimentally introduced) or foreign nucleic acids (such as viral RNAs). Dicer may cooperate with Argonaute proteins and dsRNA-binding proteins (such as RDE-4; pink) to generate siRNA duplexes that are unwound by an unknown helicase (yellow) into single-stranded siRNAs (shown in red). siRNAs bind to Argonaute proteins to form siRgonaute ribonucleoproteins and also associate with other proteins to form RISCs.

mi/siRNA function (bottom): We hypothesize that mi/siRNAs recognize their cognate RNA targets in the form of mi/siRgonaute ribonucleoproteins. If the complementarity between a mi/siRNA is partial the translation of the target mRNA is repressed (left), whereas if the complementarity is extensive, the target RNA is destabilized by endonucleolytic cleavage (center). siRgonautes may also recognize homologous DNA and silence chromatin by histone and DNA methylation (right). In addition to Argonaute proteins, mi/siRNAs may bring with them or recruit once bound to their targets other, as yet unidentified, factors (depicted as light blue, light yellow and light red vertical ovals). These hypothetical factors may play critical roles in mi/siRNA function. In some organisms (such as worms, plants or fission yeast) siRNAs may bind to their homologous RNAs and act as primers for RdRP to generate additional dsRNA.

Recent Publications

Kiriakidou M., Nelson P., Kouranov A., Fitziev P., Bouyioukos C., Z.
Mourelatos* and A. Hatzigeorgiou*. A combined computational-experimental approach predicts human microRNA targets. Genes Dev, 18:1165-78, 2004.

Nelson, P.T., Baldwin, A., Scearce, M.L., Oberholtzer, J.C., Tobias, J.W., and Z. Mourelatos*.: A novel method for microarray-based, high-throughput, gene expression profiling of microRNAs. Nature Methods, 2:155-161, 2004.

Maniataki, E and Z. Mourelatos*. A human, ATP-independent RISC assembly machine, fueled by pre-miRNAs. Genes Dev, 19:2979-2990, 2005.

Kirino Y. and Z. Mourelatos*. Mouse piwi-interacting RNAs are 2'-O-methylated at their 3'-termini. Nat Struct Mol Biol, 14:347-8, 2007.

M. Kiriakidou*, Tan, G.S., Lamprinaki S., De Plannell-Saguer M, Nelson P.T.
and Z. Mourelatos*. An mRNA m7G cap binding-like motif within human
Argonaute2 represses translation. Cell, 129:1141-51, 2007

Search PubMed for more articles

Lab

Rotation Projects

Available in all areas described above. Please contact Dr. Mourelatos.

Lab personnel:

Mariàngels De Plannel-Saguer, M.S. Graduate Student
Xuhang Liu, B.S. Graduate Student
Kristine Fortin, M.S. MD/PhD Student
Yohei Kirino, Ph.D. Postdoctoral Fellow
Namwoo Kim, Research Specialist

Nelson - Supplemental Figure 1

Nelson - Supplemental Figure 2

Nelson - Supplemental Figure 3

Nelson - Supplemental Figure 4

Nelson - Supplemental Figure 5

Nelson - Supplemental Figure 6

Nelson - Supplemental Methods

Nelson - Supplemental Table 1

Nelson - Supplemental Table 2