Amanda Poholek, PhD
Campus: 4401 Penn Ave.
Office: Rangos Research Center Rm. 8129
Pittsburgh, PA 15224
- BS, Biological Sciences, 2002, Fordham University
- PhD, Cell Biology, 2009, Yale University
- Post-doctoral Fellowship, NIAMS, NIH; Dr. John J. O'Shea
- Assistant Professor, Department of Pediatrics
- Assistant Professor, Department of Immunology
New technologies in genomic sequencing (NextGen technologies) have greatly increased our ability to study complex traits and assess how genetics and epigenetics contribute to health and disease. One application of genomic sequencing has been to understand cellular differentiation and identity, and how transcription factor networks control chromatin organization as well as transcriptomes. While some transcription factors function to directly activate genes, many also primarily function to change the accessibility of the chromatin, and create epigenetic changes that alter gene expression. My lab explores how the transcriptional repressors Bcl6 and Blimp-1 mediate changes in epigenetics that contribute to cellular differentiation of CD4 T cells, and how inappropriate epigenetic modifications may contribute to disease.
Blimp-1 and Bcl6 are expressed in a variety of cell types, most notably B cells, where they direct the differentiation of B cells into plasma cell or germinal center lineages, respectively. Both proteins function by binding to DNA and recruiting co-repressor complexes to mediate epigenetic changes that repress specific targets. Interestingly, Bcl6 and Blimp-1 can repress each other, indicating a carefully controlled transcriptional network exists wherein these two factors can shape cell fates in opposing ways. Projects in our lab work to understand what drives expression of Blimp-1 and Bcl6 in T cells, and how they modulate CD4 T cell function and identity. In addition, we are interested in understanding how these factors behave differently in different cell types.
Exploring factors that contribute to Blimp-1 and Bcl6 expression in T cells
Role of Blimp-1 and Bcl6 in altering the epigenetic landscape of CD4 T cells during differentiation
Exploring the super enhancer structure of the Blimp-1 and Bcl6 locus.
Exploring human SNPs in the Blimp-1 locus associated with disease via GWAS
Understanding enhancer regions of the Blimp-1 and Bcl6 locus and how they control cell-type specific expression
Poholek AC, Jankovic D, Villarino AV, Petermann F, Hettinga A, Shouval DS, Snapper SB, Kaech SM, Brooks SR, Vahedi G, Sher A, Kanno Y, O'Shea JJ. IL-10 induces a STAT3-dependent autoregulatory loop in Th2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Science Immunology. Nov 11, Vol.1 Issue 5. 2016. http://immunology.sciencemag.org/content/1/5/eaaf8612.full
Shih HY, Sciume G, Poholek AC, Vahedi G, Hirahara K, Villarino A, Bonelli M, Bosselut R, Kanno Y, Muljo S, O’Shea JJ. Transcriptional and epigenetic networks of helper T cells and innate lymphoid cells. Immunological Reviews. Sept;261(1):23-49. 2014. http://onlinelibrary.wiley.com/doi/10.1111/imr.12208/abstract
Nakayamada S*, Poholek AC*, Lu KT, Takahashi H, Hirahara K, Kato, M, Iwata S, Cannons JL, Schwartzberg PL, Vahedi G, Sun H, Kanno Y, O’Shea JJ. Type I Interferon induces binding of STAT1 to Bcl6: Divergent Roles of STAT-family transcription factors in the TFH cell genetic program. The Journal of Immunology. Mar 1;192(5):2156-66. 2014. http://www.jimmunol.org/content/192/5/2156.long
Vahedi G*, Poholek AC*, Hand TW, Laurence A, Kanno Y, O’Shea JJ, Hirahara K. Helper T Cell Identity and Evolution of Differential Transcriptomes and Epigenomes. Immunological Reviews. Mar;252(1):24-40. 2013. http://onlinelibrary.wiley.com/doi/10.1111/imr.12037/abstract
Poholek AC, Hansen K, Hernandez S, Eto D, Chandele A, Weinstein JS, Dong X, Odegard J, Kaech SM, Dent AL, Crotty S, Craft J. In vivo regulation of Bcl6 and T follicular helper cell development. The Journal of Immunology, 185(1):313-26, 2010. http://www.jimmunol.org/content/185/1/313.long
Johnston R*, Poholek AC*, DiToro D, Yusuf I, Eto D, Barnett B, Dent A, Craft J, and Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonist regulators of T follicular helper cell differentiation. Science. 325(5943):1006-10, 2009 http://science.sciencemag.org/content/325/5943/1006.long
- Transcription Factors
- Chromatin regulation
- T cell differentiation and effector function
- NextGen sequencing