Alex Marson, M.D., Ph.D.

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The balanced functioning of several distinct populations of specialized T cells is required to maintain immunological tolerance in the human body. T reg cells, a subset of CD4+ T cells, are essential for the prevention of autoimmunity. Treg cells enforce dominant tolerance, suppressing effector functions of other T-cell populations in vitro and in vivo. In contrast, Th17 cells, another population of CD4+ T cells, promote a pro-inflammatory state and contribute to tissue injury in human autoimmune disease. Distinct combinations of signaling pathways and transcriptional regulators drive the reciprocal developmental pathways of Treg cells and Th17 cells and, respectively, promote the suppressive and pro-inflammatory transcriptional programs of these cell types. Dysregulation of the balance between regulatory and pro-inflammatory T-cell populations appears to play an important role in the pathophysiology of human autoimmune diseases and in susceptibility to infection. Studies of the genetic programs that control the specialized functions of the cell types promise new insights into these diseases and are likely to suggest new therapeutic strategies.

 

Recent work on epigenetic reprogramming has transformed our understanding of cellular identity. Rapidly evolving genomic technologies have opened the door to new investigations of gene regulation, human genetics and screens for clinical therapies. Our work to date has demonstrated that 1) combining epigenomic maps with studies of transcription factor binding sites and expression data is a powerful approach to annotate novel transcribed and regulatory regions of the genome, 2) studying the circuitry controlled by key transcription factors can reveal genetic programs that are essential to the functioning of specialized cell types, 3) an understanding of the core transcriptional circuitry of a specific cell type can offer clues to novel approaches to reprogram cellular identity. The laboratory will build on these principles to develop enhanced understanding of the genetic circuitry controlling differentiation of T-cell lineages. We will work towards developing innovative pharmacological approaches to influence T-cell differentiation and function. These studies have potential applications in the treatment of autoimmunity, infectious diseases and in transplantation.

 

Publications

Bienvenu F, JirawatnotaiS, EliasJE, MeyerCA, MizerackaK, Marson A, Frampton GM, Cole MF, OdomD, OdajimaJ, GengY, ZagozdzonA, JecroisM, YoungRA, LiuXS, CepkoCL, GygiSP, Sicinski P. Transcriptional function of cyclin D1 upstream of Notch revealed by a "genetic-proteomic" screen. Nature. 463, 374-378 (2010).

 

Marson A , Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 135, 521-533 (2008).

 

Marson A , Foreman R, Chevalier B, Bilodeau S, Kahn M, Young RA, Jaenisch R. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell. 3, 132-135, (2008).

 

Marson A , Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 445, 931-935 (2007).

 

Daniels MJ, Marson A, Venkitaraman AR. PML bodies control the nuclear dynamics and function of the CHFR mitotic checkpoint protein. Nat Struct Mol Biol. 11, 1114-1121 (2004).