Biochemistry and Molecular Biology
Penn State Science
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Shaun Mahony

Shaun Mahony

Main Content

  • Assistant Professor of Biochemistry & Molecular Biology
404 South Frear Laboratory
University Park, PA 16802
Phone: (814) 865-3008

Research Interests

Computational biology and regulatory genomics.

 

Graduate Programs

BGBMMBMCIBS

Research Summary

My research aims to understand where transcription factors bind in the genome, and what they do once they get there. There are many forces that can affect a TF's choice of binding targets once it is introduced into the nucleus. The inherent DNA-binding preference of the protein will specify the sites that could potentially be bound, but the vast majority of high-affinity sequences will not in fact be occupied by the TF in any given cell type. Binding selectivity is thus determined by the regulatory environment of the cell: chromatin accessibility, interactions with co-factors, DNA methylation, and histone post-translational modifications all play roles in specifying the TF's binding sites. These forces are context-specific, which allows the same TF to target different binding sites in different cell types. However, a TF's choice of binding targets is only part of the equation; many bound sites do not seem to directly affect gene expression. We understand little about how enhancers can regulate genes that are thousands, sometimes millions, of bases away on the genome.

Fortunately, high-throughput sequencing assays are giving us unprecedented insight into the regulatory environment of the cell. ChIP-seq and ChIP-exo allow us to profile TF and histone modification occupancy at high resolution over the entire genome. RNA-seq lets us profile the global transcriptional activity. DNase-seq profiles the genome-wide accessibility landscape, while new assays such as ChIA-PET and Hi-C are opening a window on the three-dimensional architecture of the nucleus. The challenge will be integrating these voluminous data types into a cohesive understanding of cellular activity.

I believe that integrative machine-learning approaches that model the biological and experimental processes that generate such data will help us to understand the context-specific activity of transcription factors.

Selected Publications

  • M Iwafuchi-Doi, G Donahue, A Kakumanu, JA Watts, S Mahony, BF Pugh, D Lee, KH Kaestner, KS Zaret (2016) The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Molecular Cell 62(1): 72-91
  • C Ariyachet, A Tovaglieri, G Xiang, J Lu, MS Shah, CA Richmond, C Verbeke, DA Melton, BZ Stanger, D Mooney, RA Shivdasani, S Mahony, Q Xia, DT Breault, Q Zhou (2016). Engineered stomach tissues as a renewable source of functional beta-cells for blood glucose regulation. Cell Stem Cell 18(3):410-421
  • SS Verma, AT Frase, A Verma, SA Pendergrass, S Mahony, DW Haas, MD Ritchie (2016). Phenome-wide interaction study (PheWIS) in AIDS clinical trials group data (ACTG). Pacific Symposium on Biocomputing 21:57-68
  • GC Han, V Vinayachandran, A Bataille, B Park, KY Chan-Salis, CA Keller, M Long, S Mahony, RC Hardison, BF Pugh (2016). Genome-wide organization of GATA1 and TAL1 determined at high resolution. Molecular & Cell Biology 36(1):157-172
  • S Mahony, BF Pugh (2015). Protein-DNA binding in high resolution. Critical Reviews in Biochemistry and Molecular Biology 50(4):269-283
  • S Lodato, BJ Molyneax, E Zuccaro, LA Goff, H-H Chen, W Yuan, A Meleski, E Takahashi, S Mahony, JL Rinn, DK Gifford, P Arlotta (2014). Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nature Neuroscience 17(8):1046-54
  • S Mahony*&, MD Edwards&, EO Mazzoni, RI Sherwood, A Kakumanu, CA Morrison, H Wichterle, DK Gifford* (2014). An integrated model of multiple-condition ChIP-seq data reveals predeterminants of Cdx2 binding. PLoS Computational Biology 10(3):e1003501 (& equal contribution, *corresponding authors)
  • EJ Paik, S Mahony, RM White, EN Price, A DiBiase, B Dorjsuren, C Mosimann, AJ Davidson, DK Gifford, LI Zon (2013). A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis. Stem Cell Reports 1(5):425-436
  • EO Mazzoni*, S Mahony*, M Closser, CA Morrison, S Nedelec, DJ Williams, D An, DK Gifford, H Wichterle (2013). Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nature Neuroscience 16(9):1219-1227 (* equal contribution) 
  • EO Mazzoni*, S Mahony*, M Peljto*, T Patel, SR Thornton, S McCuine, C Reeder, LA Boyer, RA Young, DK Gifford, H Wichterle (2013). Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals . Nature Neuroscience 16(9):1191-1198 (* equal contribution) 
  • M Arbab, S Mahony, H Cho, J Chick, PA Rolfe, J Van Hoff, V Morris, S Gygi, RL Maas, DK Gifford, R Sherwood (2013). A multi-parametric flow cytometric assay to analyze DNA-protein interactions. Nucleic Acids Research 41(2):e38
  • Y Guo, S Mahony*, DK Gifford* (2012). High resolution genome wide binding event finding and motif discovery reveals transcription factor spatial binding constraints. PLoS Computational Biology 8(8):e1002638. (* corresponding authors)
  • EO Mazzoni, S Mahony, M Iacovino, CA Morrison, G Mountoufaris, M Closser, WA Whyte, RA Young, M Kyba, DK Gifford, H Wichterle (2011). Embryonic stem cell based system for the discovery and mapping of developmental transcriptional programs. Nature Methods 8(12):1056-1058.
  • S Mahony*, EO Mazzoni*, S McCuine, RA Young, H Wichterle, DK Gifford (2011). Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biology 12(1):R2. (* equal contribution)
  • Y Guo, G Papachristoudis, RC Altshuler, GK Gerber, TS Jaakkola, DK Gifford, S Mahony (2010). Discovering homotypic binding events at high spatial resolution. Bioinformatics 26(24):3028-3034.
  • H Jung, J Lacombe, EO Mazzoni, KF Leim, J Grinstein, S Mahony, D Mukopadhyay, DK Gifford, RA Young, KV Anderson, H Wichterle, JS Dasen (2010). Global control of motor neuron topography mediated by the repressive actions of a single Hox gene. Neuron 67(5):781-796 .
  • JJ Wolf, RD Dowell, S Mahony, M Rabani, DK Gifford, GR Fink (2010). Feed-forward regulation of a cell fate determinant by an RNA-binding protein generates asymmetry in yeast. Genetics 185:513-522.
  • OL Griffith, SB Montgomery, ..., S Mahony (7 of 29 authors), ..., CM Bergman, SJM Jones (2008). ORegAnno: an open-access community-driven resource for regulatory annotation. Nucleic Acids Research 36(Database issue):D107-13.
  • Y Lu, S Mahony, PV Benos, R Rosenfeld, I Simon, LL Breeden, Z Bar-Joseph (2007). Combined analysis reveals a core set of cycling genes. Genome Biology 8(7):R146.
  • S Mahony, PE Auron, PV Benos (2007). Inferring protein-DNA dependencies using motif alignments and mutual information. Bioinformatics 23(13):i297-i304.
  • S Mahony, DL Corcoran, E Feingold, PV Benos (2007). Regulatory conservation of protein coding and miRNA genes in vertebrates: lessons from the opossum genome. Genome Biology 8(5):R84.
  • TS Mikkelsen, MJ Wakefield, ..., S Mahony (37 of 64), ..., ES Lander, K Lindblad-Toh (2007). Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequence. Nature  447:167-177.