Almost every cell in the body contains essentially the same genome sequence, however differential usage of the genetic information enables cells with vastly different features and functions to be formed. The epigenome is a molecular code superimposed upon the genome that can control how genes are turned on and off, without altering the underlying DNA sequence. By modulating accessibility and usage of the information encoded in the genome, epigenetic modifications can affect gene activation and repression to execute distinct transcriptional programs and impart a stable state of transcriptional activity. Developing a comprehensive understanding of how the cell utilizes the epigenome is essential in order to both understand the critical roles it plays in cell differentiation and development, and to develop effective strategies to remedy its disruption in disease states.

DNA methylation is a central epigenetic modification that imparts an additional layer of information upon the DNA code, playing critical roles in processes including genome defense, gene regulation, development, and disease. However, fundamental questions remain regarding the processes that govern the establishment of epigenome patterns and how the cell interprets them to affect changes in chromatin structure and gene expression. Revolutionary advances in DNA sequencing technology in the past few years now allow identification of the sites of DNA methylation at single base resolution throughout entire genomes. Integration of these maps with deep molecular profiling of genome accessibility, histone modifications, and transcriptional activity are revealing unanticipated composition and dynamics in the epigenomes of complex multicellular organisms.

Ryan’s research uses advanced genomic, molecular, genetic and computational techniques to study the epigenome, including using next-generation sequencing technologies to generate whole-genome high-resolution maps of the epigenome and associated molecular processes (e.g. whole genome bisulfite sequencing, RNA-seq, ChIP-seq, ATAC-seq). His research aims to elucidate the mechanistic underpinnings of how the epigenome is established and dynamically modified, how it affects the cellular readout of the underlying genetic information, and to develop molecular tools for editing the epigenome.

• Epigenome dynamics during cellular reprogramming, differentiation, and development
• Identification of factors that read the DNA methylome
• Changes in the epigenome in neural development, stimulation, and neurological disorders
• Development of epigenome editing technologies

1. Lister R*, Mukamel EA*, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork A, Schultz MD, Tonti-Filippini J, Yu M, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341(6146):1237905.

2. Lister R*, Pelizzola M*, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315-22.  

3. Lister R*, Pelizzola M*, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471(7336):68-73. 

4.Lister R*, O’Malley RC*, Tonti-Filippini J*, Gregory BD, Berry CC, Millar AH, Ecker JR. (2008) Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133(3):523-36.

5. Roadmap Epigenomics Consortium et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317–30.

6. Xie W, Schultz M*, Lister R*, Hou Z*, Rajagopal N*, Ray P*, Whitaker JW*, Tian S*, Hawkins RD*, Leung D*, Yang H, Wang T, Lee AY, Swanson SA, Zhang J, Zhu Y, Kim A, Nery J, Urich MA, Kuan S, Yen C, Klugman S, Yu P, Suknuntha K, Propson NE, Chen H, Edsall LE, Wagner U, Li Y, Ye Z, Kulkarni A, Xuan Z, Chung W, Chi NC, Antosiewicz-Bourget J, Slukvin I, Stewart R, Zhang MQ, Wang W, Thomson JA, Ecker JR, Ren B. (2013) Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells. Cell 153(5):1134-48.  

7. Pastor WA*, Pape UJ*, Huang Y*, Henderson HR, Lister R, Ko M, McLoughlin EM, Brudno Y, Mahapatra S, Kapranov P, Tahiliani M, Daley GQ, Liu XS, Ecker JR, Milos PM, Agarwal S, Rao A. (2011) Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473(7347):394-397.

8.Mo A*, Mukamel EA*, Davis FP, Luo C, Henry GL, Picard S, Urich MA, Nery JR, Sejnowski Tj, Lister R, Eddy SR, Ecker JR, Nathans J (2015) Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain. Neuron 86:1369–84.  

9. Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, Edsall LE, Kuan S, Luu Y, Klugman S, Antosiewicz-Bourget J, Ye Z, Espinoza C, Agarwahl S, Shen L, Ruotti V, Wang W, Stewart R, Thomson JA, Ecker JR, Ren B. (2010) Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 7;6(5):479-91.        

10. Harris RA, Wang T, Coarfa C, Nagarajan RP, Hong C, Downey SL, Johnson BE, Fouse SD, Delaney A, Zhao Y, Olshen A, Ballinger T, Zhou X, Forsberg KJ, Gu J, Echipare L, O’Geen H, Lister R, Pelizzola M, Xi Y, Epstein CB, Bernstein BE, Hawkins RD, Ren B, Chung WY, Gu H, Bock C, Gnirke A, Zhang MQ, Haussler D, Ecker JR, Li W, Farnham PJ, Waterland RA, Meissner A, Marra MA, Hirst M, Milosavljevic A, Costello JF. (2010) Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nature Biotechnology 28(10):1026-1028.