Cosmas Giallourakis

Dr. Cosmas Giallourakis

Functions of RNA Chemical Modifications (Epitranscriptomes) in Health and Disease

Overview

The lab is interested in two major topics:

1) The role of post-transcriptional RNA chemical modifications (“epitranscriptomics”) on biological functions
2) The role of RNA-binding protein (RBP) interactomes in epigenetic and post-transcriptional regulatory systems implicated in human autoimmune diseases

We are interested in the intersection of RNA chemical modifications with human health and disease. It is increasingly recognized that numerous (likely 100+) chemical modifications occur on coding and non-coding RNAs of all types, including tRNAs as well as long non-coding RNAs. Furthermore, mutations in the protein machinery that places some of these types of chemical modifications lead to a number of Mendelian diseases. Indeed, we and others have begun to describe the heterogeneity and complexity of the human transcriptome as part of an RNA modification epitranscriptome code that is “written,” “erased,” and “read” by protein systems analogous to the epigenetic code of histones.

For example, N6-methyladenosine (m6A) is a widespread reversible chemical modification on RNAs implicated in the control of multiple aspects of RNA metabolism including folding, stability, trafficking, and translation. The “writing” of m6A RNA modification is accomplished via an m6A methyltransferase complex, including two known mammalian components encoded by METTL3 and METTL14. METTL3 orthologs are required for development in model organisms such as plants and flies, while mutations in the FTO m6A demethylase, or “eraser,” causes severe human development abnormalities. Applying genome-wide m6A site location analyses (m6A-seq), we revealed both evolutionarily conserved and unique m6A methylome patterns in mouse and human embryonic stem cells. Thousands of messenger and long non-coding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. Remarkably, genetic inactivation and/or depletion of mouse or human Mettl3 results in healthy cells, but leads to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC exit from self-renewal toward differentiation into several lineages in vitro and in vivo. Our results raise an important question regarding the role of m6A in differentiation and stimuli-dependent events.

In addition, it is increasingly recognized that many transcription factors interact with RNA, and many proteins thought to bind only RNA also interact with chromatin, blurring the lines between transcription factors (TFs) and RBPs. Indeed, we have shown that binding of enhancer RNAs (eRNAs) by the dual RBP and TF protein YY1 is important in enhancer functions. In addition, we have shown the importance of the 3D chromatin architecture and RBP protein CTCF in the control of immune differentiation. These results raise important questions regarding the functions and mechanisms of action of dual RBPs/TFs involved in human diseases.

 

Group Members

Cosmas Giallourakis, MD
Assistant Professor of Medicine
Harvard Medical School
Massachusetts General Hospital
55 Fruit Street
Jackson Building
Office (lab) 617-726-6122
Office (clinical) 617-726-2026
cgiallouraki@harvard.mgh.harvard.edu

 

Dr. Cosmas Giallourakis is a physician scientist and an Assistant Professor of Medicine at Harvard Medical School located in the Gastrointestinal Unit at Massachusetts General Hospital. He has an undergraduate degree in physics from MIT, a medical degree with clinical training at Yale and Harvard/MGH, and completed post-doctoral training with Frederick Alt (HHMI) at Children’s Hospital/Harvard Medical School. He has received funding from HHMI, the Crohn’s and Colitis Foundation of America, and the NIH.

 

Lab Members
Benoit Molinie, PhD
Orion Despo
Nick Van Wittenberghe
Daniel Pratt
Benjamin D. Howard

 

 

Research Projects

1) We are interested in further understanding how m6A modifications control cellular fate decisions during development and during immune responses. We are applying a combination of state-of-the-art genomic tools in vitro and in vivo to address these questions. In addition, we are developing novel tools to probe and manipulate m6A functions. Finally, we are pursuing a translational human biology component investigating the role of RNA modifications in diseases such as Crohn’s disease, ulcerative colitis, celiac disease, and eosinophilic esophagitis.

2) Genome-wide association studies have implicated multiple RNA-binding proteins and transcription factors in human autoimmune diseases such as Crohn’s disease and ulcerative colitis. We are pursuing the function of several of these proteins and how human disease susceptibility polymorphisms promote disease.

 

Publications

Selected Peer-reviewed Publications

1. Sigova AA, Abraham BJ, Ji X, Molinie B, Hannett NM, Guo YE, Jangi M, Giallourakis CC, Sharp PA, Young RA. Transcription factor trapping by RNA in gene regulatory elements. Science. 2015 Oct 29.

2. Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E, Haddad B, Daneshvar K, Carter AC, Flynn RA, Zhou C, Lim KS, Dedon P, Wernig M, Mullen AC, Xing Y, Giallourakis CC*, Chang HY. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. October 16, 2014. *(co-corresponding author; featured in Science Feb 27, 2015 news and views)

3. Giallourakis CC, Yair B, Molinie B, Cao Z, Despo O, Pratt HE, Zukerberg LE, Daly MJ, Rioux JD, Xavier RJ Genome-Wide Analysis of Immune Expression Using EST Profiling, J. Immunology, 2013 (a featured article in same JI issue)

4. Sigova AA, Mullen AC, Molinie B, Gupta S, Orlando DA, Guenther MG, Almada AE, Lin C, Sharp PA, Giallourakis CC*, Young RA. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc Natl Acad Sci. 2013 Feb 19;110(8):2876-81 (*co-corresponding author; featured in Cell Leading Edge)

5. Chiarle R, Zhang Y, Frock R, Lewis S, Molinie B, Ho R, Myers D, Choi V, Compagno M, Malkin D, Neuberg D, Monti S, Giallourakis CC*, Gostissa M, and Alt FW.  Genome-Wide Translocation Sequencing Reveals Mechanisms that Shape the Translocatome of Primary B Lymphocytes. Cell. 2011 Sep 30;147(1):107-19. (*co-corresponding author; research highlight Nature Biotechnology 29, 986 (2011))

6. Guo C, Yoon, HS Franklin A, Jain S, Ebert A, Cheng HW, Hansen E,  Despo O, Bossen C, Vettermann C, Bates JG, Richards N, Myers D, Patel H, Gallagher M, Schlissel MS, Murre C, Busslinger M, Giallourakis CC* and Alt. FW. CTCF Binding Elements Mediate Control of V(D)J Recombination. Nature. 2011 Sep 11; 477(7365): 424-30. (*co-corresponding author)

7. Giallourakis CC, Franklin A, Guo C, Cheng HL, Yoon HS, Gallagher M, Perlot T, Andzelm M, Murphy AJ, MacDonald L, Yancopoulos GD, and Alt FW. Elements between the IgH V and D clusters Influence Antisense Transcription and Lineage Specific V(D)J Recombination. Proc Natl Acad Sci. 2010 Dec 21;107(51):22207-12

 

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